Personalized Medicine for HLA-associated Drug-hypersensitivity Reactions

Mandvi Bharadwaj; Patricia Illing; Lyudmila Kostenko


Personalized Medicine. 2010;7(5):495-516. 

In This Article

HLA-class-I-associated Drug Hypersensitivities

Abacavir Hypersensitivity Syndrome & HLA-B*5701

Abacavir is a nucleoside reverse transcriptase inhibitor with potent antiretroviral activity and approved for the combination treatment of HIV. Abacavir is a prodrug that is converted in vivo to its active form, carbovir triphosphate, a guanosine analog.[30] Carbovir triphosphate inhibits viral replication by targeting reverse transcription of viral RNA into proviral DNA. A total of 5% of patients with HIV develop a life-threatening hypersensitivity reaction, known as AHS, within 6 weeks of starting therapy (average onset 11 days).[24,31] AHS is characterized clinically by symptoms including fever, rash, nausea, vomiting, abdominal pain, lethargy and malaise. The hypersensitivity reaction resolves on cessation of abacavir treatment but in a few cases, reintroduction results in a more severe hypersensitivity response and even death.[24] The reaction is thought to be instigated by abacavir-specific CD8+ T cells owing to the presence of CD8+ T-cell infiltrate in AHS-associated rash and patch testing.[25] This is supported by in vitro studies demonstrating that CD8+ T-cell depletion leads to the abrogation of abacavir-associated increases in extracellular TNF-α in AHS patients.[15]

The association of AHS with the HLA class I allele HLA-B*5701 is one of the strongest associations ever described between an immunogenetic marker and 'disease' (odds ratio >1000).[13–15,32] The Prospective Randomized Evaluation of DNA screening In a Clinical Trial 1 (PREDICT-1) trial and Study of Hypersensitivity to Abacavir and Pharmacogenetic Evaluation (SHAPE) study showed HLA-B*5701 was associated with a positive predictive value of 47.9% and a negative predictive value of 100% for AHS.[33] However, this association was initially clouded by imprecise diagnosis of AHS. It was only after the introduction of immunological confirmation of AHS via patch testing that the true strength of this association was able to be observed.[25] The veracity of this association is now supported by in vitro studies showing a role for HLA-B*5701, but not related alleles, in drug specific CD8+ T-cell stimulation.[34]

Abacavir hypersensitivity syndrome is the first HLA-associated drug hypersensitivity to have undergone trials for the use of HLA screening in hypersensitivity prevention, and constitutes a relative success story. Independent studies in a Western Australian population and a French population of mixed ethnicity have investigated efficacy of using HLA-B*5701 screening to prevent AHS by precluding positive individuals from abacavir treatment. Both studies showed that preclusion on the basis of HLA-B*5701 was able to both reduce the incidence of AHS and the incidence of inappropriate withdrawal of abacavir treatment owing to suspected AHS.[35,36] Furthermore the screening technique used in the French study was relatively cost-effective at only €27.[36] An alternative form of screening has also been suggested, using the almost complete LD between HLA-B*5701 and the rs2395029 SNP of the HCP5 gene in European populations. This test is faster and cheaper than traditional HLA sequencing techniques, however, as it is not directly identifying HLA-B*5701 it has also given positive results for related alleles in a few cases.[37]

The prevalence of AHS in different countries varies according to the genetic background of the population, probably because of ethnic variation in the frequency of the HLA-B*5701 allele.[38] For instance, AHS is less common in African–Americans[38] who are known to have a higher frequency of HLA-B*5801 and HLA-B*5702/03 subtypes, and a correspondingly lower frequency of HLA-B*5701 than patients of European descent. As a result, the number of AHS cases prevented by prescreening in these populations may not as easily justify the costs of blanket testing.

Although screening does reduce the incidence of AHS it must be remembered that the positive predictive value of HLA-B*5701 as estimated in the SHAPE study is only 47.9%.[33] This indicates that approximately 50% of HLA-B*5701 positive individuals do not develop hypersensitivity in response to abacavir, and that there must be other factors, genetic or otherwise, that determine whether an individual will develop AHS. Therefore it is apparent that whilst HLA screening drastically reduces the incidence of AHS, it may also deny treatment to individuals who could tolerate abacavir and benefit from its antiretroviral effects.