Pharmacogenetics of abacavir hypersensitivity: A systematic review and meta-analysis of the association with HLA-B*57:01
2015; Elsevier BV; Volume: 136; Issue: 4 Linguagem: Inglês
10.1016/j.jaci.2015.03.019
ISSN1097-6825
AutoresBernardo Sousa‐Pinto, João Pinto-Ramos, Cláudia Correia, Gustavo Costa, Lídia Gomes, Sara Gil‐Mata, Luís Araújo, Luís Delgado,
Tópico(s)Urticaria and Related Conditions
ResumoHypersensitivity reactions to abacavir (a nucleoside analogue inhibitor of HIV reverse transcriptase) have been associated with HLA-B*57:01 allele carriage.1Martin M.A. Kroetz D.L. Abacavir pharmacogenetics–from initial reports to standard of care.Pharmacotherapy. 2013; 33: 765-775Crossref PubMed Scopus (44) Google Scholar Although pharmacogenetic testing for HLA-B*57:01 before abacavir prescription has become routine practice, its value has been questioned after reports of low sensitivity in Hispanics and Africans.2Phillips E.J. Chung W.H. Mockenhaupt M. Roujeau J.C. Mallal S.A. Drug hypersensitivity: pharmacogenetics and clinical syndromes.J Allergy Clin Immunol. 2011; 127: S60-S66Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar Nevertheless, 2 large multiethnic studies found HLA-B*57:01 carriage to be strongly associated with abacavir hypersensitivity diagnosed by clinical criteria and patch testing in whites and blacks, suggesting that the apparent lower sensitivity of HLA-B*57:01 in populations with low prevalence of the allele was due to a higher rate of false positives.3Mallal S. Phillips E. Carosi G. Molina J.M. Workman C. Tomazic J. et al.HLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1486) Google Scholar, 4Saag M. Balu R. Phillips E. Brachman P. Martorell C. Burman W. et al.High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients.Clin Infect Dis. 2008; 46: 1111-1118Crossref PubMed Scopus (361) Google Scholar Much has been published on the association between HLA-B*57:01 carriage and abacavir-induced hypersensitivity, but a comprehensive quantitative synthesis of the evidence taking into account differences in ethnicity and diagnostic methods is lacking. We systematically assessed and quantitatively analyzed this association. Four electronic databases (MEDLINE, Scopus, Embase, and Thomson Reuters Web of Science) were searched in April 2013, using the following query: "abacavir AND (hypersensitivit* OR allerg*) AND (HLA OR genetic*)". We also searched unpublished clinical trials in the US National Institute of Health trial database (ClinicalTrials.gov) and the GlaxoSmithKline Clinical Study Register. We included case-control studies with abacavir-tolerant controls (patients with a negative skin patch test result and/or no clinical symptoms of a hypersensitivity reaction in 6 or 12 weeks after exposure) evaluating the association between HLA-B*57:01 carriage and abacavir hypersensitivity. Whenever possible, information on participants' sex, age, and ethnicity was recorded. For each outcome, quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation working group approach (see reference E1 in this article's Online Repository at www.jacionline.org). We calculated odds ratio (OR), sensitivity, specificity, and positive and negative predictive values using classical methods. For ORs, a continuity correction of 0.5 or 1.0 was applied when 1 or 2 cells had a 0 count, respectively. A random-effects meta-analysis with inverse variance weighting was used to estimate pooled OR and respective 95% CIs for the association between HLA-B*57:01 carriage and abacavir hypersensitivity. Heterogeneity was evaluated with I2 and Cochran Q statistics. An I2 value of more than 50% and a Cochran Q test P value of less than .100 were considered to represent substantial heterogeneity. Review Manager (RevMan) version 5.2 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012) was used for the meta-analysis and forest plots. For the primary outcome, results were stratified according to hypersensitivity diagnosis criteria into broad (standard) clinical criteria, strict clinical criteria, and immunological criteria (abacavir patch testing; see reference E2 in this article's Online Repository at www.jacionline.org). Strict clinical criteria were considered when cases initially defined by broader clinical criteria were reassessed, or when additional clinical criteria were used to define a subgroup of cases. Results were further stratified by ethnicity (whites, blacks, and Hispanics). Differences between subgroups were also evaluated. P values of less than .05 were considered significant. Twelve studies3Mallal S. Phillips E. Carosi G. Molina J.M. Workman C. Tomazic J. et al.HLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1486) Google Scholar, 4Saag M. Balu R. Phillips E. Brachman P. Martorell C. Burman W. et al.High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients.Clin Infect Dis. 2008; 46: 1111-1118Crossref PubMed Scopus (361) Google Scholar, 5Mallal S. Nolan D. Witt C. Masel G. Martin A.M. Moore 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: 727-732Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar, 6Hetherington S. Hughes A.R. Mosteller M. Shortino D. Baker K.L. Spreen W. et al.Genetic variations in HLA-B region and hypersensitivity reactions to abacavir.Lancet. 2002; 359: 1121-1122Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar, 7Hughes D.A. Vilar F.J. Ward C.C. Alfirevic A. Park B.K. Pirmohamed M. Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity.Pharmacogenetics. 2004; 14: 335-342Crossref PubMed Scopus (260) Google Scholar, 8Martin A.M. Nolan D. Gaudieri S. Almeida C.A. Nolan R. James I. et al.Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant.Proc Natl Acad Sci U S A. 2004; 101: 4180-4185Crossref PubMed Scopus (427) Google Scholar, 9Phillips E.J. Wong G.A. Kaul R. Shahabi K. Nolan D.A. Knowles S.R. et al.Clinical and immunogenetic correlates of abacavir hypersensitivity.AIDS. 2005; 19: 979-981Crossref PubMed Scopus (142) Google Scholar, 10Stekler J. Maenza J. Stevens C. Holte S. Malhotra U. McElrath M.J. et al.Abacavir hypersensitivity reaction in primary HIV infection.AIDS. 2006; 20: 1269-1274Crossref PubMed Scopus (38) Google Scholar, 11Rodriguez-Novoa S. Garcia-Gasco P. Blanco F. Gonzalez-Pardo G. Castellares C. Moreno V. et al.Value of the HLA-B*5701 allele to predict abacavir hypersensitivity in Spaniards.AIDS Res Hum Retroviruses. 2007; 23: 1374-1376Crossref PubMed Scopus (25) Google Scholar, 12Colombo S. Rauch A. Rotger M. Fellay J. Martinez R. Fux C. et al.The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir.J Infect Dis. 2008; 198: 864-867Crossref PubMed Scopus (86) Google Scholar, 13Rauch A. Nolan D. Thurnheer C. Fux C.A. Cavassini M. Chave J.P. et al.Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study.Antivir Ther. 2008; 13: 1019-1028PubMed Google Scholar, 14Munderi P. Snowden W.B. Walker A.S. Kityo C. Mosteller M. Kabuye G. et al.Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART.Trop Med Int Health. 2011; 16: 200-204Crossref PubMed Scopus (18) Google Scholar and 1 trial register15GlaxoSmithKline (GSK) Clinical Study Register [Internet]: Brentford (United Kingdom). 2007. Identifiers CNA30027, CNA30032, CNA30021, CNA30024, EPV40001. Final report from the analysis of candidate gene markers and genome-wide single nucleotide polymorphisms (SNPs) from two retrospective, case-control studies and three controlled clinical studies to investigate genetic polymorphisms in HIV infected subjects who developed hypersensitivity following treatment with abacavir (study RJ2006/00002/00). Result summary; updated August 2, 2007; webpage updated September 28, 2008. Available at: http://www.gsk-clinicalstudyregister.com/study/CNA30027,%20CNA30032,%20CNA30021,%20CNA30024,%20EPV40001#rs. Accessed April 27, 2013.Google Scholar (of 1195 publications and 65 trial registers found) met the inclusion criteria and were included in the meta-analysis (flowchart and funnel plot in Fig E1 of this article's Online Repository at www.jacionline.org). In total, 1234 cases and 2943 abacavir-tolerant controls were analyzed. Some cases were later reclassified after the application of stricter clinical criteria or the performance of patch tests. In brief, we compared 1223 cases defined by broad clinical criteria with 2869 controls, 315 cases defined by strict clinical criteria with 1168 controls,8Martin A.M. Nolan D. Gaudieri S. Almeida C.A. Nolan R. James I. et al.Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant.Proc Natl Acad Sci U S A. 2004; 101: 4180-4185Crossref PubMed Scopus (427) Google Scholar, 12Colombo S. Rauch A. Rotger M. Fellay J. Martinez R. Fux C. et al.The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir.J Infect Dis. 2008; 198: 864-867Crossref PubMed Scopus (86) Google Scholar, 13Rauch A. Nolan D. Thurnheer C. Fux C.A. Cavassini M. Chave J.P. et al.Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study.Antivir Ther. 2008; 13: 1019-1028PubMed Google Scholar, 15GlaxoSmithKline (GSK) Clinical Study Register [Internet]: Brentford (United Kingdom). 2007. Identifiers CNA30027, CNA30032, CNA30021, CNA30024, EPV40001. Final report from the analysis of candidate gene markers and genome-wide single nucleotide polymorphisms (SNPs) from two retrospective, case-control studies and three controlled clinical studies to investigate genetic polymorphisms in HIV infected subjects who developed hypersensitivity following treatment with abacavir (study RJ2006/00002/00). Result summary; updated August 2, 2007; webpage updated September 28, 2008. Available at: http://www.gsk-clinicalstudyregister.com/study/CNA30027,%20CNA30032,%20CNA30021,%20CNA30024,%20EPV40001#rs. Accessed April 27, 2013.Google Scholar and 81 cases with patch test confirmation with 1378 controls.3Mallal S. Phillips E. Carosi G. Molina J.M. Workman C. Tomazic J. et al.HLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1486) Google Scholar, 4Saag M. Balu R. Phillips E. Brachman P. Martorell C. Burman W. et al.High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients.Clin Infect Dis. 2008; 46: 1111-1118Crossref PubMed Scopus (361) Google Scholar, 9Phillips E.J. Wong G.A. Kaul R. Shahabi K. Nolan D.A. Knowles S.R. et al.Clinical and immunogenetic correlates of abacavir hypersensitivity.AIDS. 2005; 19: 979-981Crossref PubMed Scopus (142) Google Scholar, 13Rauch A. Nolan D. Thurnheer C. Fux C.A. Cavassini M. Chave J.P. et al.Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study.Antivir Ther. 2008; 13: 1019-1028PubMed Google Scholar Information on participants' age, sex, and ethnic group (where available) is presented in Table I.Table IFrequency of abacavir-hypersensitive cases and abacavir-tolerant controls and summary ORsReferencePopulation, n (% males; mean age)Carriers of HLA-B∗57:01 allele, n (%)OR (95% CI)Ethnic groupCasesAbacavir-tolerant controlsCasesControlsClinical: Broad criteria Mallal et al5Mallal S. Nolan D. Witt C. Masel G. Martin A.M. Moore 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: 727-732Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar18 (89; 44.8)167 (87; 42.8)14 (78)4 (2)142.6 (32.2-632.5)Whites (except for 20 controls) Hetherington et al6Hetherington S. Hughes A.R. Mosteller M. Shortino D. Baker K.L. Spreen W. et al.Genetic variations in HLA-B region and hypersensitivity reactions to abacavir.Lancet. 2002; 359: 1121-1122Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar84 (93; 40.3∗Value of median age presented. For Hetherington et al,6 the values presented correspond to the 85 cases and 115 controls initially included.)113 (91; 39.8∗Value of median age presented. For Hetherington et al,6 the values presented correspond to the 85 cases and 115 controls initially included.)37 (44)1 (1)88.2 (11.8-661.5)Multiethnic Hughes et al7Hughes D.A. Vilar F.J. Ward C.C. Alfirevic A. Park B.K. Pirmohamed M. Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity.Pharmacogenetics. 2004; 14: 335-342Crossref PubMed Scopus (260) Google Scholar13 (85; 34∗Value of median age presented. For Hetherington et al,6 the values presented correspond to the 85 cases and 115 controls initially included.)51 (90; 37∗Value of median age presented. For Hetherington et al,6 the values presented correspond to the 85 cases and 115 controls initially included.)6 (46)5 (10)7.9 (1.9-32.9)Whites (except for 4 controls) Stekler et al10Stekler J. Maenza J. Stevens C. Holte S. Malhotra U. McElrath M.J. et al.Abacavir hypersensitivity reaction in primary HIV infection.AIDS. 2006; 20: 1269-1274Crossref PubMed Scopus (38) Google Scholar9 (†Sex not specified.; 30.6)41 (†Sex not specified.; 33.5)2 (22)0 (0)27.7 (1.2-635.6)Multiethnic Rodriguez-Novoa et al11Rodriguez-Novoa S. Garcia-Gasco P. Blanco F. Gonzalez-Pardo G. Castellares C. Moreno V. et al.Value of the HLA-B*5701 allele to predict abacavir hypersensitivity in Spaniards.AIDS Res Hum Retroviruses. 2007; 23: 1374-1376Crossref PubMed Scopus (25) Google Scholar26 (†Sex not specified.; 41∗Value of median age presented. For Hetherington et al,6 the values presented correspond to the 85 cases and 115 controls initially included.)27 (†Sex not specified.; 45∗Value of median age presented. For Hetherington et al,6 the values presented correspond to the 85 cases and 115 controls initially included.)11 (42)1 (4)19.1 (2.2-162.6)Hispanic CNA30027, CNA30032, CNA30021, CNA30024, EPV40001 trials15GlaxoSmithKline (GSK) Clinical Study Register [Internet]: Brentford (United Kingdom). 2007. Identifiers CNA30027, CNA30032, CNA30021, CNA30024, EPV40001. Final report from the analysis of candidate gene markers and genome-wide single nucleotide polymorphisms (SNPs) from two retrospective, case-control studies and three controlled clinical studies to investigate genetic polymorphisms in HIV infected subjects who developed hypersensitivity following treatment with abacavir (study RJ2006/00002/00). Result summary; updated August 2, 2007; webpage updated September 28, 2008. Available at: http://www.gsk-clinicalstudyregister.com/study/CNA30027,%20CNA30032,%20CNA30021,%20CNA30024,%20EPV40001#rs. Accessed April 27, 2013.Google Scholar564 (77‡The values presented encompass "extra patients" for whom HLA-B*57:01 information was not obtained. Nevertheless, the number of these "extra patients" was never superior to 13.; 41.5‡The values presented encompass "extra patients" for whom HLA-B*57:01 information was not obtained. Nevertheless, the number of these "extra patients" was never superior to 13.)725 (74‡The values presented encompass "extra patients" for whom HLA-B*57:01 information was not obtained. Nevertheless, the number of these "extra patients" was never superior to 13.; 40.3‡The values presented encompass "extra patients" for whom HLA-B*57:01 information was not obtained. Nevertheless, the number of these "extra patients" was never superior to 13.)241§Estimated value obtained from the available data. (43)12§Estimated value obtained from the available data. (2)44.3 (24.5-80.3)Multiethnic Colombo et al12Colombo S. Rauch A. Rotger M. Fellay J. Martinez R. Fux C. et al.The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir.J Infect Dis. 2008; 198: 864-867Crossref PubMed Scopus (86) Google Scholar108†Sex not specified.Age not specified.175†Sex not specified.Age not specified.35 (30)3 (2)24.2 (7.2-80.9)Multiethnic Mallal et al3Mallal S. Phillips E. Carosi G. Molina J.M. Workman C. Tomazic J. et al.HLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1486) Google Scholar66†Sex not specified.Age not specified.781†Sex not specified.Age not specified.30 (46)19 (2)33.4 (17.2-65.0)Multiethnic Rauch et al13Rauch A. Nolan D. Thurnheer C. Fux C.A. Cavassini M. Chave J.P. et al.Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study.Antivir Ther. 2008; 13: 1019-1028PubMed Google Scholar131†Sex not specified.Age not specified.140†Sex not specified.Age not specified.41§Estimated value obtained from the available data. (31)2 (1)31.4 (7.4-133.2)Multiethnic (mostly whites) Saag et al4Saag M. Balu R. Phillips E. Brachman P. Martorell C. Burman W. et al.High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients.Clin Infect Dis. 2008; 46: 1111-1118Crossref PubMed Scopus (361) Google Scholar198 (91; 44)408 (82; 41)67 (34)10 (3)20.4 (10.2-40.7)Multiethnic Munderi et al14Munderi P. Snowden W.B. Walker A.S. Kityo C. Mosteller M. Kabuye G. et al.Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART.Trop Med Int Health. 2011; 16: 200-204Crossref PubMed Scopus (18) Google Scholar6†Sex not specified.Age not specified.241†Sex not specified.Age not specified.0 (0)0 (0)40.2 (2.2-721.1)Black (sub-Saharan) Total12232869484 (40)57 (2)32.1 (22.2-46.4)Clinical: Strict criteria Martin et al8Martin A.M. Nolan D. Gaudieri S. Almeida C.A. Nolan R. James I. et al.Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant.Proc Natl Acad Sci U S A. 2004; 101: 4180-4185Crossref PubMed Scopus (427) Google Scholar18 (83; 45.0)230 (86; 42.6)17 (94)4 (2)960.5 (101.6-9,077.1)All cases and 196 (85%) controls were of European descent CNA30027, CNA30032, CNA30021, CNA30024, EPV40001 trials15GlaxoSmithKline (GSK) Clinical Study Register [Internet]: Brentford (United Kingdom). 2007. Identifiers CNA30027, CNA30032, CNA30021, CNA30024, EPV40001. Final report from the analysis of candidate gene markers and genome-wide single nucleotide polymorphisms (SNPs) from two retrospective, case-control studies and three controlled clinical studies to investigate genetic polymorphisms in HIV infected subjects who developed hypersensitivity following treatment with abacavir (study RJ2006/00002/00). Result summary; updated August 2, 2007; webpage updated September 28, 2008. Available at: http://www.gsk-clinicalstudyregister.com/study/CNA30027,%20CNA30032,%20CNA30021,%20CNA30024,%20EPV40001#rs. Accessed April 27, 2013.Google Scholar245 (76‡The values presented encompass "extra patients" for whom HLA-B*57:01 information was not obtained. Nevertheless, the number of these "extra patients" was never superior to 13.; 41.5‡The values presented encompass "extra patients" for whom HLA-B*57:01 information was not obtained. Nevertheless, the number of these "extra patients" was never superior to 13.)623 (81‡The values presented encompass "extra patients" for whom HLA-B*57:01 information was not obtained. Nevertheless, the number of these "extra patients" was never superior to 13.; 41.8‡The values presented encompass "extra patients" for whom HLA-B*57:01 information was not obtained. Nevertheless, the number of these "extra patients" was never superior to 13.)122§Estimated value obtained from the available data. (50)12§Estimated value obtained from the available data. (2)50.5 (27.1-94.2)Multiethnic Colombo et al12Colombo S. Rauch A. Rotger M. Fellay J. Martinez R. Fux C. et al.The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir.J Infect Dis. 2008; 198: 864-867Crossref PubMed Scopus (86) Google Scholar25†Sex not specified.Age not specified.175†Sex not specified.Age not specified.20 (80)3 (2)229.3 (51.0-1,032.3)Multiethnic Rauch et al13Rauch A. Nolan D. Thurnheer C. Fux C.A. Cavassini M. Chave J.P. et al.Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study.Antivir Ther. 2008; 13: 1019-1028PubMed Google Scholar27†Sex not specified.Age not specified.140†Sex not specified.Age not specified.21§Estimated value obtained from the available data. (78)2 (1)241.5 (45.7-1,276.3)Multiethnic (mostly whites) Total3151168180 (57)21 (2)177.7 (48.4-652.0)Patch testing Phillips et al9Phillips E.J. Wong G.A. Kaul R. Shahabi K. Nolan D.A. Knowles S.R. et al.Clinical and immunogenetic correlates of abacavir hypersensitivity.AIDS. 2005; 19: 979-981Crossref PubMed Scopus (142) Google Scholar7†Sex not specified.Age not specified.11†Sex not specified.Age not specified.7 (100)1 (9)105.0 (3.7-2,948.1)Not specified Mallal et al3Mallal S. Phillips E. Carosi G. Molina J.M. Workman C. Tomazic J. et al.HLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1486) Google Scholar23†Sex not specified.Age not specified.819†Sex not specified.Age not specified.23 (100)25 (3)1464.4 (86.5-24,783.6)Multiethnic Rauch et al13Rauch A. Nolan D. Thurnheer C. Fux C.A. Cavassini M. Chave J.P. et al.Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study.Antivir Ther. 2008; 13: 1019-1028PubMed Google Scholar4†Sex not specified.Age not specified.140†Sex not specified.Age not specified.4 (100)2 (1)498.6 (20.8-11,968.0)Multiethnic (mostly whites) Saag et al4Saag M. Balu R. Phillips E. Brachman P. Martorell C. Burman W. et al.High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients.Clin Infect Dis. 2008; 46: 1111-1118Crossref PubMed Scopus (361) Google Scholar47 (91; 44)408 (82; 41)47 (100)10 (3)3605.5 (297.9-62,514.4)Multiethnic Total81137881 (100)38 (3)859.1 (189.2-3,901.4)∗ Value of median age presented. For Hetherington et al,6Hetherington S. Hughes A.R. Mosteller M. Shortino D. Baker K.L. Spreen W. et al.Genetic variations in HLA-B region and hypersensitivity reactions to abacavir.Lancet. 2002; 359: 1121-1122Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar the values presented correspond to the 85 cases and 115 controls initially included.† Sex not specified.‡ The values presented encompass "extra patients" for whom HLA-B*57:01 information was not obtained. Nevertheless, the number of these "extra patients" was never superior to 13.§ Estimated value obtained from the available data.|| Age not specified. Open table in a new tab Abacavir hypersensitivity was diagnosed on the basis of only clinical criteria in 9 studies5Mallal S. Nolan D. Witt C. Masel G. Martin A.M. Moore 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: 727-732Abstract Full Text Full Text PDF PubMed Scopus (1222) Google Scholar, 6Hetherington S. Hughes A.R. Mosteller M. Shortino D. Baker K.L. Spreen W. et al.Genetic variations in HLA-B region and hypersensitivity reactions to abacavir.Lancet. 2002; 359: 1121-1122Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar, 7Hughes D.A. Vilar F.J. Ward C.C. Alfirevic A. Park B.K. Pirmohamed M. Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity.Pharmacogenetics. 2004; 14: 335-342Crossref PubMed Scopus (260) Google Scholar, 8Martin A.M. Nolan D. Gaudieri S. Almeida C.A. Nolan R. James I. et al.Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant.Proc Natl Acad Sci U S A. 2004; 101: 4180-4185Crossref PubMed Scopus (427) Google Scholar, 10Stekler J. Maenza J. Stevens C. Holte S. Malhotra U. McElrath M.J. et al.Abacavir hypersensitivity reaction in primary HIV infection.AIDS. 2006; 20: 1269-1274Crossref PubMed Scopus (38) Google Scholar, 11Rodriguez-Novoa S. Garcia-Gasco P. Blanco F. Gonzalez-Pardo G. Castellares C. Moreno V. et al.Value of the HLA-B*5701 allele to predict abacavir hypersensitivity in Spaniards.AIDS Res Hum Retroviruses. 2007; 23: 1374-1376Crossref PubMed Scopus (25) Google Scholar, 12Colombo S. Rauch A. Rotger M. Fellay J. Martinez R. Fux C. et al.The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir.J Infect Dis. 2008; 198: 864-867Crossref PubMed Scopus (86) Google Scholar, 14Munderi P. Snowden W.B. Walker A.S. Kityo C. Mosteller M. Kabuye G. et al.Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART.Trop Med Int Health. 2011; 16: 200-204Crossref PubMed Scopus (18) Google Scholar, 15GlaxoSmithKline (GSK) Clinical Study Register [Internet]: Brentford (United Kingdom). 2007. Identifiers CNA30027, CNA30032, CNA30021, CNA30024, EPV40001. Final report from the analysis of candidate gene markers and genome-wide single nucleotide polymorphisms (SNPs) from two retrospective, case-control studies and three controlled clinical studies to investigate genetic polymorphisms in HIV infected subjects who developed hypersensitivity following treatment with abacavir (study RJ2006/00002/00). Result summary; updated August 2, 2007; webpage updated September 28, 2008. Available at: http://www.gsk-clinicalstudyregister.com/study/CNA30027,%20CNA30032,%20CNA30021,%20CNA30024,%20EPV40001#rs. Accessed April 27, 2013.Google Scholar and clinically and immunologically (at least in some participants) in 4 studies.3Mallal S. Phillips E. Carosi G. Molina J.M. Workman C. Tomazic J. et al.HLA-B*5701 screening for hypersensitivity to abacavir.N Engl J Med. 2008; 358: 568-579Crossref PubMed Scopus (1486) Google Scholar, 4Saag M. Balu R. Phillips E. Brachman P. Martorell C. Burman W. et al.High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients.Clin Infect Dis. 2008; 46: 1111-1118Crossref PubMed Scopus (361) Google Scholar, 9Phillips E.J. Wong G.A. Kaul R. Shahabi K. Nolan D.A. Knowles S.R. et al.Clinical and immunogenetic correlates of abacavir hypersensitivity.AIDS. 2005; 19: 979-981Crossref PubMed Scopus (142) Google Scholar, 13Rauch A. Nolan D. Thurnheer C. Fux C.A. Cavassini M. Chave J.P. et al.Refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the Swiss HIV Cohort Study.Antivir Ther. 2008; 13: 1019-1028PubMed Google Scholar All studies except 1, in which no participants carried the HLA-B*57:01 allele,14Munderi P. Snowden W.B. Walker A.S. Kityo C. Mosteller M. Kabuye G. et al.Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART.Trop Med Int Health. 2011; 16: 200-204Crossref PubMed Scopus (18) Google Scholar found a significant association between HLA-B*57:01 expression and abacavir hypersensitivity. The association was significant regardless of the diagnostic criteria used. The OR was 32.1 (95% CI, 22.2-46.4; P < .001) (I2 = 14%; P = .31) in studies that used broad clinical criteria, 177.7 (95% CI, 48.4-652.0; P < .001) (I2 = 71%; P = .02) in studies that used strict clinical criteria, and 859.1 (95% CI, 189.2-3901.4; P < .001) (I2 = 0%; P = .43) in studies that used patch test confirmation (Fig 1). In the subgroup analysis, HLA-B*57:01 carriage was significantly more strongly associated with immunologically confirmed abacavir hypersensitivity than with hypersensitivity diagnosed by broad clinical criteria (P < .001), but no significant differences were observed when strict clinical criteria were applied (P = .12). Significant differences were found on comparing broad and strict criteria (P = .01). In the ethnic subgroup analysis, HLA-B*57:01 carriage was significantly associated with abacavir hypersensitivity in white patients diagnosed both clinically (OR, 31.9; 95% CI, 21.7-47.0; P < .001) (I2 = 0%; P = .46) and immunologically (OR, 1,507.0; 95% CI, 200.8-11,311.3; P < .001) (I2 = 0%; P = .81) (Fig 1). An OR of 11.1 (95% CI, 3.8-32.6; P < .001) (I2 = 0%; P = .43) was observed in black patients with clinically diagnosed abacavir hypersensitivity. An analysis restricted to US studies (in which most black patients are probably African-American) yielded an OR of 9.0 (95% CI, 2.8-28.8; P < .001) (I2 = 0%; P = .39). Patch testing was performed in just 1 study of blacks (OR, 899.8; 95% CI, 38.5-21,045.3). A statistically significant association was also observed for HLA-B*57:01 carriage in Hispanics (OR, 17.6; 95% CI, 3.9-80.4; P < .001) (I2 = 0%; P = .61), in whom hypersensitivity was diagnosed using only clinical criteria. No significant differences were found between ethnic groups when clinically diagnosed hypersensitivity was analyzed (whites vs Hispanics, P = .46; whites vs blacks, P = .07; Hispanics vs blacks, P = .63). In conclusion, HLA-B*57:01 carriage is significantly associated with abacavir-induced hypersensitivity reactions in whites, blacks, and Hispanics, with stronger associations observed when hypersensitivity was diagnosed immunologically (patch testing) or using strict clinical criteria. On comparing studies that applied the same diagnostic criteria, no significant differences were observed between ethnic groups, confirming the hypothesis that the apparent lower sensitivity of HLA-B*57:01 in some ethnic groups mirrors a high rate of false-positive diagnoses.2Phillips E.J. Chung W.H. Mockenhaupt M. Roujeau J.C. Mallal S.A. Drug hypersensitivity: pharmacogenetics and clinical syndromes.J Allergy Clin Immunol. 2011; 127: S60-S66Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar This supports the need for applying more rigorous criteria when diagnosing abacavir hypersensitivity—in fact, there were no significant differences when comparing patch test and strict clinical criteria in the subgroup analysis despite the significant heterogeneity of the latter. Although HLA-B*57:01 might play a less pivotal role in abacavir hypersensitivity in nonwhites,14Munderi P. Snowden W.B. Walker A.S. Kityo C. Mosteller M. Kabuye G. et al.Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART.Trop Med Int Health. 2011; 16: 200-204Crossref PubMed Scopus (18) Google Scholar our analysis revealed a shortage of studies assessing such populations. Furthermore, our results for blacks must be interpreted with care because the quality of evidence was particularly low (see Table E1 in this article's Online Repository), and all the studies but one were from the United States. In addition, 2 of the studies had 2 cells with a 0 count, requiring a continuity correction of 1, which may have distorted results. Nevertheless, our results support a generalized screening policy because pharmacogenetic testing had a sensitivity and negative predictive value of 100% for patch test (corresponding to confirmed cases). Yet, its 70% positive predictive value highlights the need for studies of additional genetic risk factors in populations with a low prevalence of HLA-B*57:01 to develop genetic tests with an optimal cost-benefit balance. Table E1Quality assessment of evidence using the GRADE approachSubgroup studiedNo. of studiesRisk of biasInconsistencyIndirectnessImprecisionOR (95% CI)Quality of evidence∗GRADE Working Group grades of evidence—High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.Diagnosis by broad clinical criteria11Serious†Colombo et al12 and Munderi et al14 did not describe the demographic characteristics of the cases and controls.No serious inconsistencyNo serious indirectnessNo serious imprecision32.1 (22.2-46.4) (strong association)⊕⊕ΟΟ LowDiagnosis by strict clinical criteria4Serious†Colombo et al12 and Munderi et al14 did not describe the demographic characteristics of the cases and controls.Serious‡Significant heterogeneity (P = .02; I2 = 71%).No serious indirectnessNo serious imprecision177.7 (48.4-652.0) (strong association)⊕ΟΟΟ Very lowDiagnosis by patch testing5No serious risk of biasNo serious inconsistencyNo serious indirectnessNo serious imprecision859.1 (189.2-3901.4) (strong association)⊕⊕⊕Ο ModerateDiagnosis by clinical criteria: whites6No serious risk of biasNo serious inconsistencyNo serious indirectnessNo serious imprecision31.9 (21.7-47.0) (strong association)⊕⊕⊕Ο ModerateDiagnosis by clinical criteria: Africans and patients of African descent3Serious†Colombo et al12 and Munderi et al14 did not describe the demographic characteristics of the cases and controls.No serious inconsistencyNo serious indirectnessNo serious imprecision11.1 (3.8-32.6) (strong association)⊕⊕ΟΟ LowDiagnosis by clinical criteria: Hispanics3No serious risk of biasNo serious inconsistencyNo serious indirectnessNo serious imprecision17.6 (3.9-80.4) (strong association)⊕⊕⊕Ο ModerateDiagnosis by patch testing: whites2No serious risk of biasNo serious inconsistencyNo serious indirectnessNo serious imprecision1507.1 (200.8-11311.3) (strong association)⊕⊕⊕Ο ModerateGRADE, Grading of Recommendations Assessment, Development and Evaluation.∗ GRADE Working Group grades of evidence—High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.† Colombo et al12Colombo S. Rauch A. Rotger M. Fellay J. Martinez R. Fux C. et al.The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir.J Infect Dis. 2008; 198: 864-867Crossref PubMed Scopus (86) Google Scholar and Munderi et al14Munderi P. Snowden W.B. Walker A.S. Kityo C. Mosteller M. Kabuye G. et al.Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART.Trop Med Int Health. 2011; 16: 200-204Crossref PubMed Scopus (18) Google Scholar did not describe the demographic characteristics of the cases and controls.‡ Significant heterogeneity (P = .02; I2 = 71%). Open table in a new tab GRADE, Grading of Recommendations Assessment, Development and Evaluation.
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