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Pharmacogentics
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Pharmacogentics is a new area of research in HIV. Essentially, it consists of trying to find if there is a connection between a person's genetic makeup and there reaction to drugs such as the development of side effects, toxicities, their antiviral response to therapy, and perhaps numerous additional types of connections between a person's genes and diseases and therapy for those diseases. The AIDS Clinical Trials Group, pharmaceutical companies, and researchers are looking into this field to understand these potential connections. At the December 2001 ICAAC meeting, their was a talk about the potential connection between a person's genes and their viral load response to protease inhibitors. Perhaps a certain gene may affect how much of a protease inhibitor drug can get into a cell. Since a PI acts inside the CD4 cell, if more drug gets in and stays there, perhaps the drug will be more effective. If there are changes over years in this inflow and outflow of drug into cells, perhaps a person may lose the antiviral effectiveness of this drug. At this time, these are theories being researched, but the field of Pharmacogenetics appears to be getting much attention.
One of the main hopes from researching this field is that we could identify who may be predisposed to certain side effects or toxicities from a particular drug. If researchers can identify a gene that can be related to causing a certain drug toxicity, perhaps they can find a test for this gene that a person can have performed. Then the person can avoid this drug if they test postitive for the gene. One of the first real developments in this field were research reports presented at the Retrovirus Conference presenting about a gene found to potentially cause abacavir hypersenstivity. If this research is confirmed patients may one day be able to take a gene test to see if they are predisposed to this reaction to abacavir.
The hope is that research will lead to numerous developments like this one related to abacavir. For example, perhaps a predisposing genetic makeup can be found for lipoatrophy or insulin resistance. This may be used to guide HIV therapy choices. But this research is in its infancy and may take 5 years or more to begin to show perhaps real clinically applicable results.
At Retrovirus there were two presentations from preliminary and initial findings of a potential gene that if present in a person may lead to abacavir hypersenstivity. At this point these findings are early. There is no test yet to predict hypersentivity to abacavir and its premature to predict if researchers will find such a connection and test. But this research presents a look into the future of research and the field of pharmacogenetics.
The Presence of HLA-B*5701, -DRB1*0701, and -DQ3 Is Highly Predictive of Hypersensitivity to the HIV Reverse Transcriptase Inhibitor Abacavir
Simon Mallal from Australia reported on a gene that may lead to abacavir hypersentivity. As you know, the use of abacavir, an HIV nucleoside analogue reverse transcriptase inhibitor, is complicated by a potentially life-threatening hypersensitivity syndrome in approximately 5% of cases. Genetic factors influencing the immune response to abacavir may confer susceptibility.
Mallal performed major histocompatibility complex region typing in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases and was excluded in 167 individuals with >6 weeks exposure (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity.
HLA-B*5701 (a type of gene) was present in 78% of patients with abacavir hypersensitivity, and 2.3% of abacavir-tolerant patients (OR = 117, p<0.0001), while the HLA-DRB1*0701 and -DQ3 combination was found in 72% of
hypersensitive and 3.0% of tolerant patients (OR = 72, p< 0.0001). HLA-B*5701 and HLA-DRB1*0701+DQ3 were present in combination in 72% hypersensitive and 0% tolerant patients (OR = 822, p<0.0001). Other potential MHC markers
also present on the 57.1 ancestral haplotype (D6S1014*137, C4A6, D6S273*135, TNF -238A, MICA*194, MIB*344) and confirmed the presence of haplotype-specific linkage, and mapped potential genetic relationships.
Mallal concluded that in our population, withholding abacavir in those with HLA-B*5701, -DRB1*0701, and -DQ3 should reduce the prevalence of hypersensitivity from 9% to 2.5% without inappropriately denying abacavir to any patient. These findings need to be confirmed in other populations before such a practice could be generalised. Furthermore, testing for the haplotype is not 100% sensitive and therefore, cannot be considered a screening test, and current clinical practices should continue to underpin the management of abacavir hypersensitivity.
HLA-B57 and TNF-alpha Variants Associated with Hypersensitivity Reactions to Abacavir among HIV-1-Positive Subjects
Seth Hetherington from Glaxo Smith Kline presented a second oral talk on his research. He said features of the syndrome are consistent with an immunologic process possibly influenced by genetic factors. 90% of cases occur within the first 6 weeks of therapy.
GSK researchers conducted a retrospective case-control proof of principle study in which they enrolled patients to compare selected genetic changes in HIV-infected subjects who developed symptoms consistent with hypersensitivity (cases) to subjects who did not (controls). All subjects participated in clinical trials with abacavir. All cases had clinical histories compatible with hypersensitivity to abacavir, and all controls had received abacavir for a minimum of 6 weeks. Cases and controls (1:2 ratio) were matched by race, gender, and when possible CD4+ cell count, age, and antiviral therapy. Conditional logistic regression and recursive partitioning analyses were performed.
Evaluable data are available on genetic makeup for 114 candidate gene markers and HLA A, B, and DR . Overall, 92% of subjects were male, 74% Caucasian, and 14% were black. Multiple gene changes were identified within associated with susceptibility to hypersensitivity. Analysis identified a known polymorphism of TNF-alpha (-238A) among 25 of 58 (43%) cases compared to 7 of 99 (7%) controls (p<0.001). In addition, HLA-B57 was present in 39 of 84 (46%) cases vs 4 of 113 (3.5%) controls (p<0.001).
Hetherington emphasized that although data support the role of genetic factors in hypersensitivity reactions, a causal relationship is not established. HLA typing as a prognostic screening tool is problematic due to false positive rate, lack of data in many key demographic groups (testing has so far been done mostly in whites and not blacks). Since these tests and genes were not fully predictive, they must not be used as a diagnostic test when symptoms suggest a hypersensitivity reaction. The gene status of the patient should not be used to alter the clinical management of a hypersensitivity reaction.
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