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Method of screening for drug hypersensitivity reactionRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic AcidMethod of screening for drug hypersensitivity reaction description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070148641, Method of screening for drug hypersensitivity reaction. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority from U.S. Provisional Application No. 60/314,026 filed Aug. 21, 2001 and U.S. Provisional Application No. 60/336,850 filed Oct. 30, 2001. BACKGROUND [0002] Hypersensitivity reactions (HSR) are unexpected, immune (allergy)-like reactions that occur in a minority of patients treated with antiretroviral therapy. No single symptom or laboratory test has been found to predict or diagnose such events. Common symptoms, which appear in combinations, include fever, rash, gastrointestinal reactions, severe fatigue, and respiratory symptoms. Such hypersensitivity reactions constitute a distinct clinical entity and are not the simple rashes (mild rashes without systemic symptoms) that are common reactions to many drugs. Hypersensitivity reactions resolve on discontinuation of the causative drug, but return on reinitiation. The exact mechanism of hypersensitivity reactions is unknown. [0003] Antiretroviral therapy has been demonstrated to be effective in the treatment of individuals infected with Human Immunodeficiency Virus (HIV) or diagnosed with Acquired Immune Deficiency Syndrome (AIDS). Therapy with combinations of antiretroviral agents can prolong survival and decrease the risk of complications of HIV-1 infection. Adverse reactions may occur with any antiretroviral agent, some with the potential to cause severe morbidity and mortality. (See e.g., Samuel et al., Antiretroviral Therapy 2000, Arch. Pharm. Res. 23:425 (2000); Carr et al., Lancet 356:1423 (2000)). Common, and usually less severe, adverse reactions include nausea, headache, fatigue, diarrhea and non-severe skin rashes. Less common but sometimes severe adverse reactions to antiretroviral agents include severe skin rashes, pancreatitis, lactic acidosis, and hypersensitivity reactions. [0004] Hypersensitivity reactions to abacavir (Ziagen) have been reported to occur among approximately 5% of patients who receive this agent alone or in combination with other antiretroviral agents (note that Ziagen is indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents). Discontinuation of abacavir results in resolution of the symptoms of the hypersensitivity reaction. Continued administration of abacavir in the face of an ongoing reaction or reinstitution of abacavir in patients with a prior history of a reaction may result in a sudden, severe, and potentially fatal reaction. [0005] A screening test to identify subjects at increased risk for a hypersensitivity reaction to a pharmaceutical compound would be useful in clinical medicine. SUMMARY OF THE INVENTION [0006] A first aspect of the present invention is a method of identifying genotypes that confer a increased or decreased risk for a hypersensitivity reaction to abacavir in human subjects. In a population of test subjects, each subject is genotyped for polymorphisms in a candidate gene, such as the TNFalpha (TNF.alpha.) gene, MICA, MICB, and/or HLA genes. A therapeutic regime of abacavir is administered to each subject (either prior to, concomitant with, or after genotyping of the subject), and test subjects that exhibit (or exhibited) clinical signs of a hypersensitivity reaction to abacavir are identified. The genotypes of the test subjects at polymorphic sites in the candidate genes are correlated with the occurrence of clinical signs of hypersensitivity reaction, to determine which genotypes are associated with an increased or decreased risk of hypersensitivity reaction (compared to other genotypes or to a general population that has not been stratified by genotype). [0007] A further aspect of the present invention is a method of determining whether an individual is at increased risk of experiencing a hypersensitivity reaction to abacavir, by determining whether the individual has a genotype that is associated with an increased risk of hypersensitivity reaction, compared to the risk in subjects with alternate genotypes. [0008] A further aspect of the present invention is a method of determining whether an individual is at decreased risk of experiencing a hypersensitivity reaction to abacavir, by determining whether the individual has a genotype that is associated with a decreased risk of hypersensitivity reaction, compared to the risk in subjects with alternate genotypes. [0009] A further aspect of the present invention is a method of screening a human subject as an aid in assessing suitability to abacavir administration, by determining whether the subject has a TNF.alpha. genotype that has been associated with an increased risk of hypersensitivity reaction to abacavir compared to the risk in subjects with alternate TNF.alpha. genotypes. The presence of such a TNF.alpha. genotype indicates the subject is at increased risk for a hypersensitivity reaction to abacavir. [0010] A further aspect of the present invention is a method of screening a human subject as an aid in assessing suitability to abacavir administration, by determining whether the subject has an HLA genotype that has been associated with an increased risk of hypersensitivity reaction to abacavir compared to the risk in subjects with alternate HLA genotypes. The presence of such an HLA genotype indicates the subject is at increased risk for hypersensitivity reaction to abacavir. [0011] A further aspect of the present invention is a method of treating a human subject with abacavir, by first genotyping the subject to detect the presence or absence of the HLA-B57 allele, and then administering abacavir if the HLA-B57 allele is not detected. [0012] A further aspect of the present invention is a method of screening a human subject as an aid in predicting the subject's risk of experiencing a hypersensitivity reaction to a therapeutic regime of abacavir, by genotyping a sample of DNA from the subject to determine the presence of a polymorphism in the TNF.alpha. gene, where the polymorphism has previously been associated with an increased risk of abacavir HSR compared to the risk of HSR associated with alternate TNF.alpha. polymorphisms. Detecting the presence of a TNF.alpha. genotype that has been associated with an increased incidence of hypersensitivity reaction to abacavir (compared to the incidence of abacavir HSR associated with other TNF.alpha. genotypes) indicates that the subject is at an increased risk of a hypersensitivity reaction to abacavir. [0013] A further aspect of the present invention is a method of screening a human subject as an aid in predicting the subject's risk of experiencing a hypersensitivity reaction to a therapeutic regime of abacavir, by genotyping a sample of DNA from the subject to determine the presence of a polymorphism in an HLA gene, where the polymorphism has previously been associated with an increased risk of abacavir HSR compared to the risk of HSR associated with alternate polymorphisms. The presence of an HLA genotype that has been associated with an increased incidence of hypersensitivity reaction to abacavir (compared to the incidence of abacavir HSR associated with other HLA genotypes) indicates that the subject is at an increased risk of a hypersensitivity reaction to abacavir. [0014] A further aspect of the present invention is a method of identifying human genotypes associated with an increased risk for a hypersensitivity reaction to abacavir, by genotyping each member of a population of test subjects for at least one polymorphism in the TNF.alpha. gene, administering a therapeutic regime of abacavir to each test subject, and identifying test subjects that exhibit clinical signs of a hypersensitivity reaction to abacavir. Correlating TNF.alpha. genotypes with the occurrence of clinical signs of hypersensitivity reaction, will determine which genotypes are associated with an increased risk of hypersensitivity reaction to abacavir (compared to the other detected genotypes). [0015] A further aspect of the present invention is a method of identifying human genotypes associated with an increased risk for a hypersensitivity reaction to abacavir, by genotyping each member of a population of test subjects for at least one polymorphism in an HLA gene, administering a therapeutic regime of abacavir to each test subject, and identifying test subjects that exhibit clinical signs of a hypersensitivity reaction to abacavir. Correlating HLA genotypes with the occurrence of clinical signs of hypersensitivity reaction, will determine which genotypes are associated with an increased risk of hypersensitivity reaction to abacavir (compared to the other detected genotypes). [0016] A further aspect of the present invention is a method of administering or prescribing abacavir to reduce the incidence of abacavir hypersensitivity reaction. The method comprises selecting, based on genotype status, a treatment population from a larger starting population of subjects who have a condition suitable for treatment with abacavir. The treatment population is selected to increase the percentage of subjects in the treatment population who have a genotype that has been associated with reduced risk of abacavir hypersensitivity reaction (the increased percentage of subjects in the treatment population is relative to the percentage of subjects in the starting population). Alternatively, the treatment population is selected to decrease the percentage of subjects in the treatment population who have a genotype that has been associated with increased risk of abacavir hypersensitivity reaction. Abacavir is then administered to the selected treatment population, thereby reducing the incidence of abacavir HSR in the treated population compared to the incidence that would have been expected to occur had abacavir been administered to the larger starting population. The `selection` may occur by any suitable process as will be apparent to those skilled in the art. Examples of suitable selection methods include genetically screening starting population subjects, or otherwise classifying subjects by genotype (e.g., where a subject's genotype is known, genetic testing need not be repeated); or otherwise regulating access to abacavir to decrease the number of subjects in the treatment population who have genotypes that have been associated with an increased risk of abacavir HSR. One such genotype is the HLA-B57 allele, where the treatment population would be selected to minimize the occurrence of the HLA-B57 allele in the treatment population. Alternatively, the genotype of interest may be the TNF G(-237)A polymorphism, where the treatment population is selected to minimize the occurrence of the A allele. DETAILED DISCUSSION [0017] Anti-retroviral therapy in HIV-infected patients often comprises the use of multiple types of antiretroviral agents, including protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTI) and nucleoside reverse transcriptase inhibitors (NRTI). Abacavir is a synthetic purine nucleoside analogue that is commercially available as abacavir sulfate (ZIAGEN.RTM.; GlaxoSmithKline), and that is used in combination with other antiretroviral agents to treat HIV-infected subjects. Abacavir is an inhibitor (NRTI) of the HIV-1 reverse transcriptase that contains an unsaturated cyclopentene ring in place of the 2'deoxyriboside of natural deoxynucleosides, and contains a cyclopropylamino group. The chemical name of abacavir sulfate is (cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-met- hanol sulfate (salt) (2:1). [0018] Hypersensitivity reactions are idiosyncratic events of a presumed immunologic nature that occur with a broad range of pharmacological compounds. In the context of abacavir administration, hypersensitivity reactions to abacavir can be serious and progress to become life-threatening (Clay et al., Ann Pharmacotherapy 34(2):247 (2000); Staszewski et al., AIDS 12:F197 (1998)). In clinical trials, hypersensitivity to abacavir has occurred among approximately 5% of subjects. [0019] Signs and symptoms of a hypersensitivity reaction to abacavir include (but are not limited to) fever, skin rash, fatigue, gastrointestinal symptoms (including nausea, vomiting, diarrhea, abdominal pain), and respiratory symptoms (including pharyngitis, dyspnea and cough). Additional signs and symptoms include malaise, lethargy, myalgia, myolysis, arthralgia, edema, headache and paresthesia. Physical findings include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations). The rash associated with hypersensitivity reaction usually appears maculopapular or urticarial, but the appearance may be variable; up to 30% of hypersensitivity reactions have occurred without rash. Laboratory abnormalities include elevated liver function tests, increased creatine phosphokinase or creatinine, and lymphopenia. See Package Insert, Ziagen (abacavir sulfate), Glaxo Wellcome, Research Triangle Park, N.C. (1998); Clay et al., Management Protocol for Abacavir-related Hypersensitivity Reaction, Ann. Pharmacotherapy 34(2):247 (2000). Clay et al. state that the presence of rash alone does not warrant discontinuation of abacavir unless other systemic symptoms of hypersensitivity reaction occur. 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