Abacavir&HLA-B*5701



Scientific Studies & Publication
Abacavir & HLA-B*5701
2011 \| 2010 \| 2009 \| 2008 \| 2004

2011
Title 1: Practical Ethics: Establishing a Pathway to Benefit for Complex Pharmacogenomic Tests Clinical pharmacology & Therapeutics \| VOLUME 90 NUMBER 1 \| JULY 2011 SB Haga and W Burke Pharmacogenomic tests offer a promising strategy to improve the safety and efficacy of drug treatment. Compelling examples, such as HLA -B*5701 testing to identify patients at risk for abacavirassociated hypersensitivity, are already changing clinical care. However, the level of evidence required to establish clinical utility is often the subject of debate. Determining the most efficient and effective pathway to benefit for a given test is therefore both a practical and an ethical concern.


*Title 2: Association of the genetic marker for abacavir hypersensitivity HLA-B5701 with HCP5 rs2395029 in Mexican Mestizos** Pharmacogenomics (2011) 12(6), 809–814 Francisco Sanchez- Giron, Beatriz Villegas- Torres, Karla Jaramillo- Villafuerte, Irma Silva-Zolezzi, Juan Carlos Fernandez-Lopez, Gerardo Jimenez- Sanchez & Alessandra Carnevale Prospective screening for HLA-B5701 decreases or abolishes abacavir hypersensitivity reaction. In Caucasians, the HLA complex protein 5 gene (HCP5) rs2395029(G) allele is in complete linkage disequilibrium (LD) with HLA-B5701 (r2 = 1). Aim: To assess the frequency of HLA-B5701 and its LD with HCP5 rs2395029(G) allele, to extend our knowledge of genetic variants that are of critical relevance for the development of pharmacogenetics in Mexico. Materials & methods: We genotyped 300 Mexican Mestizos from the Mexican Genome Diversity Project. HLA-B5701 genotyping was performed using a DNA sequencing method. HCP5 rs2395029 was genotyped using a custom TaqMan® SNP genotyping assay and confirmed by direct sequencing. Genotypes for 14 SNPs in the HCP5 region were retrieved from the Mexican Genome Diversity Project database for LD analysis. Results: HLA-B5701 carrier frequency was 2% and the allelic frequency was 0.010. Haplotype analysis revealed that HLA-B5701 and the HCP5 rs2395029(G) allele are in complete LD (r2 = 1) in this Mexican Mestizos sample. Conclusion: It is feasible to have a pharmacogenetic program based on HCP5 rs2395029 genotyping as a screening tool with confirmation of HLA-B*5701 carriage by sequenciation, to prevent abacavir hypersensitivity reaction in Mexican patients before initiating abacavir therapy.


Title 3: Delayed drug hypersensitivity: models of T-cell stimulation British Journal of Clinical Pharmacology 2011 71:5 / 701–707 Jacqueline Adam, Werner J. Pichler & Daniel Yerly Drug-induced hypersensitivity reactions can cause a variety of serious diseases by involving drug-specific T-cells.Many of these reactions have been explained by the hapten concept, which postulates that small chemical compounds need to bind covalently to proteins to be recognized by the immune system. Due to their chemical reactivity, haptens stimulate the innate immunity by binding covalently to endogenous proteins and form so called hapten-carrier complexes, which are antigenic and induce T-cell responses. In recent years, a new concept has been developed since drug-induced hypersensitivity reactions were also observed with chemically unreactive drugs. This concept implies direct and reversible interactions of the drug between T-cell receptors (TCR) and major histocompatability complex (MHC) molecules. Therefore it was termed pharmacological interactions with immune receptors (p-I concept). Early observations on drug reacting T-cell clones (TCC) let believe that drugs bind first to the T-cell receptor since HLA molecules could be exchanged without affecting the drug reactivity. However, MHC molecules were always required for full activation of TCC. According to its strong HLA-B*5701 association, recent data on abacavir suggest that a drug could first bind to the peptide binding groove of the MHC molecule. The thereby modified HLA molecule can then be recognized by specific T-cells. Consequently, two types of reactions based on the p-i mechanism may occur: on the one hand, drugs might preferentially bind directly to the TCR, whereas in defined cases with strong HLA association, drugs might bind directly to the MHC molecule.


Title 4: Hypersensitivity reactions to HIV therapy British Journal of Clinical Pharmacology 2011 71:5 / 659-671 Mas Chaponda & Munir Pirmohamed Many drugs used for the treatment of HIV disease (including the associated opportunistic infections) can cause drug hypersensitivity reactions, which vary in severity, clinical manifestations and frequency.These reactions are not only seen with the older compounds, but also with the newer more recently introduced drugs.The pathogenesis is unclear in most cases, but there is increasing evidence to support that many of these are mediated through a combination of immunologic and genetic factors through the major histocompatibility complex (MHC).Genetic predisposition to the occurrence of these allergic reactions has been shown for some of the drugs, notably abacavir hypersensitivity which is strongly associated with the class I MHC allele,HLA-B*5701.Testing before the prescription of abacavir has been shown to be of clinical utility, has resulted in a change in the drug label, is now recommended in clinical guidelines and is practiced in most Western countries. For most other drugs, however, there are no good methods of prevention, and clinical monitoring with appropriate (usually supportive and symptomatic) treatment is required.There is a need to undertake further research in this area to increase our understanding of the mechanisms, which may lead to better preventive strategies through the development of predictive genetic biomarkers or through guiding the design of drugs less likely to cause these types of adverse drug reactions.


Title 5: Pharmacogenetics: From Bench to Byte— An Update of Guidelines Clinical pharmacology & Therapeutics VOLUME 89 NUMBER 5 may 2011 JJ Swen, M Nijenhuis, A de Boer, L Grandia2, AH Maitland-van der Zee, H Mulder, GAPJM Rongen, RHN van Schaik, T Schalekamp3, DJ Touw, J van der Weide, B Wilffert, VHM Deneer and H-J Guchelaar Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).


*Title 6: Pharmacogenetic screening: HLA-B5701 vs. CYP2B6 G516T** HIV Medicine (2011), 12, 255–256 AWC Lin, W-C Yam, H-Y Lam, S To, D Chan, KCW Chan and S-S Lee The prevalences of the human leucocyte antigen (HLA)-B5701 and cytochrome P450 2B6 (CYP2B6) 516 polymorphisms were studied concurrently in a cohort of 234 Han Chinese HIV-infected patients. The prevalence of HLA-B5701 was low at 0.4%, compared with 6% for the CYP2B6 TT genotype. The allelic frequency of 516 G ! T was 0.24. Our results suggest that screening for the CYP2B6 516 polymorphism in the Chinese population may be useful, whereas screening for HLA-B5701 may not be, because of its very low prevalence, but this requires further study. Studies are also needed to validate the clinical effectiveness of CYP2B6 screening. Pharmacogenetic testing has become important as a means of optimizing drug treatment in clinical practice. A good example of this is the use of HLA-B5701 screening to prevent the abacavir hypersensitivity reaction in HIV-infected patients. Such a screening strategy has the potential to be used for the testing of other genetic markers. The CYP450 2B6 gene is a promising candidate for testing in this way.


Title 7: Drug hypersensitivity: Pharmacogenetics and clinical syndromes J ALLERGY CLIN IMMUNOL MARCH 2011 VOLUME 127, NUMBER 3 Elizabeth J. Phillips, MD, Wen-Hung Chung, MD, PhD, Maja Mockenhaupt, MD, PhD, Jean-Claude Roujeau, MD and Simon A. Mallal, MBBS Severe cutaneous adverse reactions include syndromes such as drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). An important advance has been the discovery of associations between HLA alleles and many of these syndromes, including abacavir-associated hypersensitivity reaction, allopurinol-associated DRESS/DIHS and SJS/TEN, and SJS/TEN associated with aromatic amine anticonvulsants. These HLA associations have created the promise for prevention through screening and have additionally shed further light on the immunopathogenesis of severe cutaneous adverse reactions. The rollout of HLA-B5701 into routine clinical practice as a genetic screening test to prevent abacavir hypersensitivity provides a translational roadmap for other drugs. Numerous hurdles exist in the widespread translation of several other drugs, such as carbamazepine, in which the positive predictive value of HLA-B1502 is low and the negative predictive value of HLA-B*1502 for SJS/TEN might not be 100% in all ethnic.


Title 8: Abacavir and lamivudine for the treatment of human immunodeficiency virus Expert Opin. Pharmacother. (2011) 12(13):2129-2138 Giuliano Rizzardini & Patrizia Zucchi Introduction: The introduction of combination antiretroviral therapy (cART) in 1996 dramatically changed the survival and the quality of life of people living with human immunodeficiency virus (HIV). Viral replication can be controlled by using a combination of more than 30 licensed drugs. Despite the fact that many advances have been made in the last 20 years of experience with antiretrovirals, certain needs remain to be addressed, such as the presence of chronic inflammation, the long-term side effects of newly introduced drugs and eradication. Abacavir (ABC) and lamivudine (3TC) are licensed in a fixed-dose combination to be administered once daily with other antiretroviral agents for the treatment of HIV. Areas covered: This article provides an extensive review of the evidence on the combination of ABC 600 mg and 3TC 300 mg. Specifically, it discusses the chemistry -- including the phrarmacodynamics, resistance to treatment, pharmacokinetics and metabolism -- and formulations available. It also looks at clinical efficacy, including safety and tolerability. Expert opinion: In the last few years, new data regarding human leukocyte antigen (HLA) B*5701 testing to prevent the hypersensitivity reaction due to ABC have been presented, providing a landmark in the management of adverse events in HIV, and later a previously unexpected correlation of the recent exposure to ABC with an increased risk of cardiovascular disease. This review presents the current situation with regard to the long-term efficacy and safety data on the ABC/3TC combination.


*Title 9: Novel sensitive, specific and rapid pharmacogenomic test for the prediction of abacavir hypersensitivity reaction: HLA-B57:01 detection by real-time PCR Pharmacogenomics (2011) 12(4), 567–576 Cinzia Dello Russo, Lucia Lisi, Alessia Lofaro, Simona Di Giambenedetto, Bruno Federico, Giordano Madeddu, Marianna Salerno, Maria Stella Mura, Antonella Pirazzoli, Andrea de Luca, Roberto Cauda & Pierluigi Navarra Aim:** International HIV treatment guidelines recommend HLA-B57:01 typing before abacavir administration, in order to reduce the incidence of abacavir hypersensitivity reactions, the major cause of early therapy discontinuation. A fast, sensitive and specific test for HLA-B57:01 detection has been developed in the present study.
Materials & methods: Two sets of sequence-specific primers were designed, and amplification rapidly detected by real-time PCR.
Results: A total of 108 samples were analyzed in a single-blind fashion, and 41 samples were identified as positive. Complete agreement, with k = 1 (standard error = 0.0962, p < 0.0001), was found, with a validated methodology used in the EPI109367 clinical trial funded by GlaxoSmithKline, and consisting of low-resolution sequence-specific oligonucleotide PCR, followed by high-resolution sequence-specific oligonucleotide PCR carried out on the HLA-B*57-positive samples.
Conclusion: We provided a detailed characterization of a novel HLA-B*57:01 screening test, which can be easily implemented by those laboratories already involved in the detection of viral load and virus genotyping.


*Title 10: Frequency of HLA B5701 allele carriers in abacavir treated-HIV infected patients and controls from northeastern Brazil** CLINICS 2011;66(8):1485-1487 Sergio Crovella, Lara Biller, Sergio Santos, Ana Salustiano, Lucas Brandao, Rafael Guimaraes, Ludovica Segat, Jose´ Luiz de Lima Filho, Luiz Claudio Arraes The hypersensitivity reaction to Abacavir has been reportedly associated with the presence of the major histocompatibility complex class I allele HLA-B5701 and this association has been confirmed in several replication studies in different ethnic groups of HIV-positive patients. In our study, we searched for the presence of HLA B5701 in 96 HIV-positive patients treated with Abacavir and in 243 healthy subjects from Northeastern Brazil (Recife, Pernambuco) to verify the percentage of HLA B*5701 allele carriers in HIV patients and in the general population from Northeast Brazil. This area is known to harbor a tri-hybrid population resulting from contributing African (44%), Caucasian (34%), and native American (22%) genomes.


2010
Title 1 : Pharmacogenetics of drug hypersensitivity Pharmacogenomics. 2010 July ; 11(7): 973–987. doi:10.2217/pgs.10.77. Elizabeth J Phillips and Simon A Mallal Drug hypersensitivity reactions and severe cutaneous adverse drug reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysis, are examples of serious adverse drug reactions mediated through a combination of metabolic and immunological mechanisms that could traditionally not have been predicted based on the pharmacological characteristics of the drug alone. The discovery of new associations between these syndromes and specific HLA has created the promise that risk for these reactions could be predicted through pharmacogenetic screening, thereby avoiding serious morbidity and mortality associated with these types of drug reactions. Despite this, several hurdles exist in the translation of these associations into pharmacogenetic tests that could be routinely used in the clinical setting. HLA-B*5701 screening to prevent abacavir hypersensitivity syndrome is an example of a test now in widespread routine clinical use in the developed world.


*Title 2 : Introduction of pharmacogenetic screening for the human leucocyte antigen (HLA) B5701 variant in Polish HIV-infected patients HIV Medicine (2010), 11, 345–348 M Parczewski, M Leszczyszyn-Pynka, A Wnuk, A Urban˜ ska, K Fuksin˜ska, D Bander and A Boron˜-Kaczmarska Objective:** Prospective pharmacogenetic screening for the human leucocyte antigen (HLA) B5701 allele can significantly reduce the number of cases of abacavir-related hypersensitivity among HIV-infected patients treated with this drug. The aim of this study was to establish the frequency of the HLA B5701 variant in HIV-infected Poles.
Methods: The sequence-specific primer (SSP) test was used to assess the feasibility of the introduction of such testing in clinical practice. For this purpose, 234 randomly selected HIV-positive patients were screened using a low-resolution SSP assay, with HLA B*5701-positive results confirmed using a high-resolution test.
Results andConclusions: The HLA B*5701 variant was found in 11 of 234 subjects (4.7%). Testing with the selected method proved quick and reliable.


*Title 3 : HLA-B5701 frequency in Chilean HIV-infected patients and in general population** [Braz J Infect Dis 2010;14(5):510-512]©Elsevier Editora Ltda. Helena Poggi, Alejandra Vera, Marcela Lagos, Sandra Solari, Luis Rodríguez P, Carlos M Pérez It has been demonstrated that HLA-B5701 screening reduces the risk for hypersensitivity reaction to abacavir in HIV-infected patients. Since B5701 prevalence varies among different populations, it is important to determine the carrier frequency prior to its use for the screening of HIV-infected patients. The aim of this study was to determine HLA-B5701 carrier frequency in Chilean general population and HIV-infected patients referred for B5701 typing. For that purpose 300 blood bank donors and 492 abacavir-naïve HIV-infected patients from Chile were screened for B5701 by a sequence specifi c primer PCR. We detected 14/300 (4.7%) B57-positive individuals in the Chilean general population, 11 (3.7%) were B5701 positive, and 3 (1%) had another subtype. All were heterozygous, thus a B5701 allele frequency of 2% was determined. Eleven of 492 (2.2 %) HIV-patients carried a B5701 allele. The difference between these frequencies is probably due to slow progression of HIV infection in HLA-B5701 carriers, thus less patients would require antiretroviral therapy and B5701 typing. Considering the usefulness of B5701 screening, its prevalence in the Chilean general population, and the availability of a validated method, we conclude that HLA-B*5701 typing in Chilean HIV-infected patients about to initiate abacavir treatment is strongly recommended.


Title 4 : Abacavir/lamivudine combination in the treatment of HIV: a review Therapeutics and Clinical Risk Management 2010:6 83–94 Geetha Sivasubramanian, Emmanuel Frempong-Manso, Rodger D MacArthur Abacavir has been at the center of research and clinical interest in the last two years. The frequency of the associated abacavir hypersensitivity syndrome has decreased substantially since the introduction of routine testing for the HLA-B*5701 allele; the activity of the drug in HIV-infected persons with HIV RNA values more than 100,000 copies/mL has been questioned; the possible increased risk of myocardial infarction after recent exposure to abacavir has been debated; and the drug has been moved from the “recommended” category to the “alternative” category in several guidelines. Still, the drug remains a useful agent in combination with other drugs, including lamivudine, for the treatment of HIV infection. This review will focus on the pharmacokinetics, activity, side effects, and resistance profile of both abacavir and lamivudine, including a thorough review of all of the recent studies relevant to both drugs.


2009
*Title 1 : Should HLA-B5701 Screening Be Performed in Every Ethnic Group before Starting Abacavir?** Clinical Infectious Diseases 2009; 48:365–7 Wan Beom Park, Pyoeng Gyun Choe, Kyoung-Ho Song, Shinwon Lee, Hee-Chang Jang, Jae Hyun Jeon, Sang-Won Park, Myoung Hee Park, Myoung-don Oh, and Kang Won Choe Human leukocyte antigen allele (HLA)–B5701 is associated with abacavir hypersensitivity. However, the carriage rate of HLA-B5701 has rarely been studied in Asians. In 534 Korean patients with human immunodeficiency virus infection, HLA-B5701 status was determined by polymerase chain reaction with HLA-B5701–specific primers. No patients had the HLA-B*5701 allele (95% confidence interval, 0%–0.7%). This explains the paucity of immunologically confirmed cases of abacavir hypersensitivity in Koreans.


*Title 2 : HLA-B5701 screening prior to abacavir prescription: Clinical and laboratory aspects** Critical Reviews in Clinical Laboratory Science, 2009; 46(3): 153–165 David Nolan This review focuses on the development of HLA-B*5701 genetic screening as a means of preventing drug hypersensitivity reactions caused by a commonly prescribed antiretroviral drug, abacavir. This strongly predictive genetic association, which in many respects represents a test case for the clinical application of pharmacogenetics, highlights the fine specificity of HLA-restricted immunity, here directed against a drug-specific antigen rather than an allogeneic molecule (as occurs in transplantation) or a pathogenic organism (as in viral infection). However, this example also demonstrates that successful implementation of pharmacogenetic screening requires that a range of criteria be adequately addressed. These include pharmaceutical factors (e.g. lack of alternative treatments with similar or improved cost effectiveness, safety, and efficacy), clinical factors (e.g. accurate diagnosis of the adverse event, in this case provided by clinical diagnostic criteria and adjunctive epicutaneous patch testing), sufficient objective evidence of the test’s predictive value and generalizability (in this case provided by the first large-scale randomized trial of a pharmacogenetic test), as well as availability of quality-assured laboratory services that are responsive to the needs of targeted genetic screening. This example is intended to serve as a precedent for other pharmacogenetic screening strategies, particularly those aimed at reducing rates of serious drug hypersensitivity reactions in clinical practice.


*Title 3 : Correlation, in previously treated HIV-1 positive patients, between hypersensitivity reaction to abacavir and the presence of the HLA-B5701 allele Farm Hosp. 2009;33(3):155-60 Noemí Pérez Prior, Amparo Rocher Milla, Enrique Soler Company, Juan Flores Cid, and Benjamín Sarria Chust Introduction:** Hypersensitivity reaction to abacavir (a powerful inverse transcriptase inhibitor) is a serious adverse effect that limits its use in antiretroviral treatment and requires a high level of clinical surveillance. Certain haplotypes of the primary histocompatibility complex proteins (HLA-B5701) are very significant predictors of the risk of hypersensitivity to this drug. The purpose of this study is to identify the cases where a probable hypersensitivity reaction to abacavir presented the HLA-B5701 allele.
Method: A retrospective study was conducted in all HIV-1 positive adult patients infected treated with abacavir between January 2000 and December 2007, in Department 6 of the Agencia Valenciana de Salud (Valencia Health Agency). The adverse effects developed by the patients were collected to determine which cases presented a probable clinically diagnosed hypersensitivity reaction. Finally, these 39 patients were screened for HLA-B*5701.
Results: In total, 323 patients were treated with abacavir between 2000 and 2007. The treatment was discontinued in 12.1% (n=39 patients) presenting a hypersensitivity reaction. Nine (23.1%) of these were HLA-B*5701 positive. Eight patients presented skin rash and positivity was observed in only single patient with gastrointestinal symptoms and fever.
Conclusions: The administration of the HLA-B*5701 gene test may be of benefit in clinical practice, because it prevents diagnostic errors of the hypersensitivity reaction and enables more accurate interpretation of the symptoms.


2008
*Title 1 : HLA-B5701 Screening for Hypersensitivity to Abacavir N Engl J Med 2008;358:568-79. Simon Mallal, M.B., B.S., Elizabeth Phillips, M.D., Giampiero Carosi, M.D., Jean-Michel Molina, M.D., Cassy Workman, M.B., B.S., Janez Tomažič, M.D., Eva Jägel-Guedes, M.D., Sorin Rugina, M.D., Oleg Kozyrev, M.D., Juan Flores Cid, M.D., Phillip Hay, M.B., B.S., David Nolan, M.B., B.S., Sara Hughes, M.Sc., Arlene Hughes, Ph.D., Susanna Ryan, Ph.D., Nicholas Fitch, Ph.D., Daren Thorborn, Ph.D., and Alastair Benbow, M.B., B.S., for the PREDICT-1 Study Team Background:** Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B5701 allele. This study was designed to establish the effectiveness of prospective HLA-B5701 screening to prevent the hypersensitivity reaction to abacavir.
Methods: This double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B5701 screening, with exclusion of HLA-B5701–positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir.
Results: The prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001).
Conclusions: HLA-B5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug.


2004
*Title 1 : Predisposition to abacavir hypersensitivity conferred by HLA-B5701 and a haplotypic Hsp70-Hom variant** PNAS March 23, 2004 vol. 101 no. 12, 4180–4185 Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLAB* 5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8 T cell depletion. These data indicate that the concurrence of HLA-B5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B5701-restricted immune response to abacavir.