By Kevin E. Noonan --
One of the promises of the genomics revolution of the late 20th Century is the advent of personalized medicine. The belief was (and is) that the unfolding understanding of genetic variation stemming from sequence analysis of genes known or discovered to be involved in an individual's response to a drug would permit physicians to identify which patients should (and more importantly) should not receive a particular drug. In addition to these benefits for individuals, the prospect of understanding how genetic variation affected drug responses was also believed to provide a way to screen populations of drug trial participants, to avoid clinical trial failures for pharmaceutical lead compounds because the trial population contained individuals whose genetic makeup was inappropriate for the drug.
Like a great deal of the biotechnology revolution, these prospects have not generally come to fruition. There have been some applications of the personalized medicine paradigm (excessive toxicity of Camptosar® (irinotecan) for colon carcinoma is associated with the *28 variant of UGT1A1 enzyme, for example), but by and large most patients and their physicians do not test their genotype before taking (or prescribing) a drug. This makes those instances where the genetic component is taken into account more noteworthy; the latest example involves GlaxoSmithKline's drug abacavir (structure at right), a reverse transcriptase inhibitor drug used widely for infection with the human immunodeficiency virus and its sequellae, acquired immune deficiency syndrome. It is sold as Ziagen®, and is also a component in two other AIDS medications, Trizivir® (abacavir sulfate/lamivudine/zidovudine) and Epzicom® (abacavir sulfate/lamivudine).
The reason for genotype testing is simple: the Food and Drug Administration has determined that administering the drug to people having the 'wrong' genotype can be life-threatening. The problem is a severe allergic reaction in people with a particular variant gene in the human immunohistocompatibility complex. This variant, HLA-B*5701, is associated with more than a 15-fold increase in the incidence of a hypersensitivity reaction (from 4% to 61%) when these patients are administered the drug, and prescreening for the variant reduces the incidence of hypersensitivity reactions from 7.8% to 3.4%. Symptoms of the reaction range from the merely annoying (rash, nausea) to the severe (fever, breathing difficulties).
The FDA posted the following notice on its website earlier today:
FDA informed healthcare professionals that serious and sometimes fatal hypersensitivity reactions (HSR) caused by abacavir therapy are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*5701. FDA reviewed data from two studies that support a recommendation for pre-therapy screening for the presence of the HLA-B*5701 allele and the selection of alternative therapy in positive subjects. Genetic tests for HLA-B*5701 are available and all patients should be screened for the HLA-B*5701 allele before starting or restarting treatment with abacavir or abacavir-containing medications. Development of clinically suspected abacavir HSR requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients negative for HLA-B*5701.
The association of this genetic variant with the hypersensitivity reaction was first reported in February by a multinational group including GSK researchers, in an article in the New England Journal of Medicine (see "HLA-B*5701 Screening for Hypersensitivity to Abacavir").
The drug currently bears this warning:
WARNINGS
Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity reactions have been associated with ZIAGEN (abacavir sulfate). Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: (1) fever, (2) rash, (3) gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain), (4) constitutional (including generalized malaise, fatigue, or achiness), and (5) respiratory (including dyspnea, cough, or pharyngitis). Discontinue ZIAGEN as soon as a hypersensitivity reaction is suspected. Permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible. Following a hypersensitivity reaction to abacavir, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
Reintroduction of ZIAGEN or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions. Such reactions can occur within hours (see WARNINGS and PRECAUTIONS: INFORMATION FOR PATIENTS).
Lactic Acidosis and Severe Hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including ZIAGEN and other antiretrovirals (see WARNINGS).
The good news for GSK is that the percentage of the population bearing this variant is small -- about 5%. The company also benefits from having a way of preventing this small percentage of patients from being harmed by the drug. This may offset the negative consequences stemming from the FDA's intention to include the genotype advisory in a "black box" label for the drug, which alerts physicians to potentially significant side-effects but also can inhibit physicians from prescribing the drug in the first place. Having a way to determine whether a particular patient falls outside the proscribed patient population should be sufficiently reassuring to physicians that prescriptions should not plummet as a consequence of the new labeling.
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