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HLA-B*5701 screening for hypersensitivity to Abacavir
Get PDFBackground
Hypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 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-B*5701 screening, with exclusion of HLA-B*5701–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-B*5701 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-B*5701 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
High sensitivity of human leukocyte antigen–B*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients
Get PDFBackground. Although the human leukocyte antigen (HLA)-B*5701 is highly associated with a hypersensitivity reaction (HSR) to abacavir (ABC), variable sensitivities have been reported when clinical data alone have been used to define an ABC HSR. This study evaluated the sensitivity of detection of the HLA-B*5701 allele as a marker of ABC HSRs in both white and black patients, using skin patch testing to supplement clinical diagnosis. Methods. White and black patients, identified through chart review, were classified as having received a diagnosis of an ABC HSR based on clinical findings only (a clinically suspected ABC HSR) or based on clinical findings and a positive skin patch test result (an immunologically confirmed [IC] ABC HSR). Control subjects were racially matched subjects who tolerated ABC for ≥12 weeks without experiencing an ABC HSR. Patients and control subjects were tested for the presence of HLA-B*5701. Sensitivity, specificity, and odds ratios for the detection of HLA-B*5701 as a marker for an ABC HSR were calculated for white and black participants. Results. Forty-two (32.3%) of 130 white patients and 5 (7.2%) of 69 black patients who met the criteria for clinically suspected HSRs had IC HSRs. All 42 white patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 1945; 95% confidence interval, 110-34,352). Among all white patients with clinically suspected HSRs, sensitivity was 44% (57 of 130 patients tested positive for HLA-B*5701); specificity among white control subjects was 96%. Five of 5 black patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 900; 95% confidence interval, 38-21,045). Among black patients with clinically suspected HSRs, the sensitivity was 14% (10 of 69 tested positive for HLA-B*5701); specificity among black control subjects was 99%. Conclusions. Although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B*5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both races
A simple screening approach to reduce B*5701-associated abacavir hypersensitivity on the basis of sequence variation in HIV reverse transcriptase
Get PDFBackground. Abacavir hypersensitivity is strongly associated with the human leukocyte antigen (HLA)–B*5701 allele; however, the cost of routine high-resolution HLA typing before initiation of therapy remains prohibitive. We propose a simple approach to reduce B*5701-associated abacavir hypersensitivity based on the screening of human immunodeficiency virus (HIV) reverse transcriptase (RT) for a signature B*5701-associated cytotoxic T lymphocyte escape mutation at RT codon 245.
Methods. The correlation between HLA-B*5701 and RT codon 245 variation was investigated in 392 HIV-infected, antiretroviral-naive adults who were initiating highly active antiretroviral therapy. The relationship between codon 245 variation and premature abacavir discontinuation was investigated in a larger cohort of treated individuals (n = 982). Associations between HLA-B*5701 and codon 245 variants were determined using Fisher's exact test or the χ2 test.
Results. A very strong association between HLA-B*5701 and RT codon 245 variation was observed. Only 1 (4.2%) of 24 subjects with B*5701 harbored virus with the clade B “wild-type” amino acid 245V, compared with 278 (75.5%) of 368 who did not have B*5701 (P < .001). The sensitivity and specificity of codon 245 substitutions for predicting HLA-B*5701 were 96% and 75%, respectively, and the positive and negative predictive values were 20% and 99.6%, respectively. This association remained robust even after antiretroviral treatment was administered (negative predictive value, 100%; n = 269). In abacavir-treated individuals (n = 982), codon 245 substitutions were predictive of premature abacavir discontinuation (P = .02).
Conclusions. As HIV RT sequence is incidentally obtained as a part of routine drug-resistance testing, the examination of sequence variation at RT codon 245 could be adopted as a simple, low-cost screening method to identify individuals who could be safely treated with abacavir and/or who could benefit from HLA characterization
Prospective genetic screening decreases the incidence of Abacavir hypersensitivity reactions in the Western Australian HIV cohort study
Get PDFAbacavir therapy is associated with significant drug hypersensitivity in ∼8% of recipients, with retrospective studies indicating a strong genetic association with the HLA-B*5701 allelle. In this prospective study, involving 260 abacavir-naive individuals (7.7% of whom were positive for HLA-B*5701), we confirm the usefulness of genetic risk stratification, with no cases of abacavir hypersensitivity among 148 HLA-B*5701–negative recipients
Carriage of HLA-B*5701 and a haplotypic Hsp70-Hom variant is associated with a Class I MHC-restricted hypersensitivity response to abacavir
Get PDFBackground: Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use has a significant genetic component. We have shown that the presence of HLA-B*5701 strongly predicts abacavir (ABC) hypersensitivity, particularly in combination with other allelic markers specific to the 57.1 ancestral haplotype, and identified a potential susceptibility locus within a 300-kb region between MEGT1 and C4A6 loci in the central MHC. Here we used fine recombinant haplotype mapping to identity the susceptibility loci.
Methods: We studied 248 consecutive ABC-exposed individuals, representing full ascertainment of ABC use in the Western Australian HIV Cohort study. Hypersensitivity was definite in 18 cases (7.3%); 230 tolerant controls were identified, utilizing an updated clinical classification that included corroborative epicutaneous skin patch test. Patients were typed for genetic markers using standard molecular techniques. Intracellular measurement of TNF (3-color flow cytometry) and intracellular localization of Hsp70 and HLA-B57 (confocal microscopy) were undertaken on abacavir exposed ex vivo polymorphic blood mononuclear cell (PBMC) cultures.
Results: Recombinant mapping in patients with allelic markers of the 57.1 ancestral haplotype suggest a susceptibility locus within the Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases and 1.7% of controls (OR 960, p <0.00001). A haplotypic non-synonymous polymorphism of Hsp70-Hom (HspA1L, M493T) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (OR 3893, p <0.00001). The Hsp70-Hom M493T allele was present in 22% of controls (OR 60, p <0.00001), suggesting that the combination of HLA-B*5701 and Hsp70-Hom M493T conferred susceptibility. Individuals hypersensitive to ABC exhibited a significantly higher proportion of monocytes expressing TNF in response to ex vivo ABC stimulation, which was abrogated, on depletion of CD8+ T cells from whole blood. Increased intracellular expression of Hsp70 and HLA-B57 molecules in abacavir exposed ex vivo cultured PBMCs was observed in hypersensitive patients compared with controls. Hsp70 and HLA-B57 molecules co-localized within discrete vesicles.
Conclusions: These data indicate that the presence of HLA-B*5701 and Hsp70-Hom M493T are predisposing factors in the development of hypersensitivity to ABC, and implicates them in the generation of a Class I-restricted pathogenic immune response
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HLA-B*5701 frequency n Chilean HIV-infected patients and in general population
Get PDFAbstractIt has been demonstrated that HLA-B*5701 screening reduces the risk for hypersensitivity reaction to abacavir in HIV-infected patients. Since B*5701 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-B*5701 carrier frequency in Chilean general population and HIV-infected patients referred for B*5701 typing. For that purpose 300 blood bank donors and 492 abacavir-naïve HIV-infected patients from Chile were screened for B*5701 by a sequence specific primer PCR. We detected 14/300 (4.7%) B*57-positive individuals in the Chilean general population, 11 (3.7%) were B*5701 positive, and 3 (1%) had another subtype. All were heterozygous, thus a B*5701 allele frequency of 2% was determined. Eleven of 492 (2.2%) HIV-patients carried a B*5701 allele. The difference between these frequencies is probably due to slow progression of HIV infection in HLA-B*5701 carriers, thus less patients would require antiretroviral therapy and B*5701 typing. Considering the usefulness of B*5701 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
HLA-B*5701 Allele in HIV-infected Indian Children and its Association with Abacavir Hypersensitivity
No full textAbstract
Objective
To determine the prevalence of HLA-B*5701 allele in HIV-infected children, and to find its association with Abacavir hypersensitivity.
Methods
Children (2 to 18 y) already on, or to be initiated on Abacavir were included for PCR sequencing to detect HLA-B*5701. Outcome measures were: proportion with HLA B*5701 allele and hypersensitivity with Abacavir. Abacavir was stopped if patient tested positive for HLA-B*5701 allele.
Results
100 children (median age 11 y) were enrolled; 10 were already on Abacavir. HLA-B*5701 positivity was observed in 11 (11%) children. Two of these 11 children developed hypersensitivity after initiation of Abacavir. Abacavir was thereafter stopped in all who tested HLA-B*5701 positive, irrespective of the development of hypersensitivity reaction.
Conclusions
HLA-B*5701 allele was present in 11 (11%) of HIV-infected children, of which two developed Abacavir hypersensitivity. None of the patients without the allele developed hypersensitivity.
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HLA-B*5701 Taqman assay for abacavir sensitivity: Application to PREDICT-1 trial
No full textAim: Around 5% of HIV infected patients treated with the HIV drug abacavir experience an allergic hypersensitive response within 6 weeks. Genetic association studies have shown that the HLA-B*5701 allele is highly associated with abacavir hypersensitivity (Mallal et al 2002). and studies of in vitro T cell responses to abacavir pulsed APC indicate that the B*5701 allele is a causal determinant of allergic hypersensitivity (Chessman et al 2007). Our aim was to develop a real-time PCR method of detecting the B*5701 allele on the same automated platform (Cobas AmpliPrep/Cobas TaqMan;CAP/CTM) currently used for determining HIV viral load.
Methods: The B*5701 CTM is a single tube, 2 channel research assay using 2 pairs of primers and Hex- and Fam-labeled Taqman probes. A Hex labeled control probe binds to the exon 2 of all HLA-B alleles. The exon 3 primers and the Fam labeled probe are B*5701 specific.
Results: This assay was used to determine the B*5701 status of 1956 DNA samples from the PREDICT-1 study (Mallal et al 2008). This study demonstrated the clinical utility of B*5701 screening prior to abacavir treatment. HLA-B*5701 status was independently determined by using SSOP followed by SBT for HLA-B57 positive samples (LabCorp) as well as SBT single step full allelic typing (Perth). The Roche CTM HLA-B*5701 results are fully concordant with the sequencing results. Currently, this research assay can be run on whole blood in the same integrated CAP/CTM platform used for measuring HIV viral load.
Conclusions: The HLA-B*5701 CAP/CTM assay is a valuable research screening test for determining HLA-B*5701 status in abacavir-naï ve HIV patients
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