Abacavir hypersensitivity reaction (AHSR) affects 4-8% of patients with HIV-1 infection within the first 6 weeks of starting abacavir. It is usually characterised by fever, rash, abdominal pains and lethargy. Symptoms related to abacavir hypersensitivity reaction deteriorate with continued therapy and improve within 72 hours of abacavir discontinuation. Rechallenging with abacavir after a hypersensitivity reaction usually results in recurrence of symptoms within hours and with the potential to be fatal.[36]
GlaxoSmithKline and Western Australian investigators have independently found a strong association between an HLA type and the risk of developing abacavir hypersensitivity. Martin et al. [37] showed a strong association between carriage of the 57.1 ancestral haplotype of major histocompatibility complex (MHC) genes and abacavir hypersensitivity in HIV patients using recombinant haplotype mapping. They found the occurrence of the HLA-B*57:01 allele and a haplotypic variant of the Hsp70-Hom allele represented a highly predictive susceptibility marker for abacavir hypersensitivity. Genetic tests involving HLA-B*57:01 alone or in combination with the Hsp70-Hom M493T variant reduced the prevalence of definite abacavir hypersensitivity in the population predominantly of European origin from 8% to 0.4%. When using HLA-B*57:01 alone, an estimated 1.6% of the tested population would be inappropriately denied access to abacavir, however, testing for the presence of both HLA-B*57:01 and the Hsp70-Hom M493T variant would reduce this percentage to 0.4%. On the basis of many such studies it is recommended that HLA-B*57:01 screening occur before commencement of abacavir-containing regimens and that HLA-B*57:01–positive patients should not be prescribed abacavir.
A retrospective study by GlaxoSmithKline of patients with abacavir hypersensitivity reaction also found a strong association between the hypersensitivity reaction and HLA-B*57:01. They identified a strong association between a point mutation (SNP) in the tumour necrosis factor-∝ (TNF-∝) gene and abacavir hypersensitivity reaction. However, this association is thought to be a secondary rather than a primary association as the HLA-B57 and TNF-∝ SNP genes are linked.
Molecular assays have been developed to identify the HLA-B*57:01 allele associated with abacavir hypersensitivity reaction. The EUROArray HLA-B57:01 Direct assay provides molecular genetic determination of HLA-B*57:01 alleles in human genomic DNA. The test provides fast and simple HLA-B*57:01 detection, encompassing all currently known HLA-B*57:01 alleles in one test reaction. The procedure is performed directly on whole blood samples and does not require a separate DNA isolation. Genomic DNA of blood cells is prepared for PCR by diluting the blood with the extraction solution provided in the test kit and incubating it for one minute. In the first reaction step, a section of the HLA-B gene and a β-globin gene fragment as positive control are amplified from the thus produced extract or, alternatively, from a patient genomic DNA sample using the polymerase chain reaction (PCR). All PCR products are labelled with a fluorescence dye as they are produced. In the second reaction step, the products are analysed using a microarray containing immobilised probes which are complementary to the amplified DNA. The specific binding (hybridisation) of the fluorescing PCR product to the corresponding microarray spot is detected using a special microarray scanner (by EUROIMMUN). If an HLA-B*57:01 allele is present in a patient DNA sample, a fluorescence signal is generated at the specific HLA-B*57:01 spots. The spot signals are evaluated automatically using the EUROArrayScan software.39