Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Concepts in Pharmacogenomics and Personalized Medicine
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in about 5–8% of patients treated with the drug and generally presents within six
weeks of drug initiation. 54,55 Symptoms of an abacavir-induced HSR may include
skin rash, fever, malaise, gastrointestinal symptoms, and respiratory symptoms.
Severe forms of the skin rash may result in Stevens–Johnson syndrome (SJS), toxic
epidermal necrolysis (TEN), or systemic lupus erythematosus. 56 If a patient experiences
an HSR, abacavir is discontinued and symptoms generally resolve within
72 hours. 57 Restarting abacavir is contraindicated as this may result in a potentially
life-threatening reaction. 55
Gene/Allele of Interest and Functional Effect
It appears that the presence of allele human leukocyte antigen (HLA)-B*5701 confers a
high risk of abacavir-induced HSR. Of those with HLA-B*5701-negative allele status,
less than 1% of individuals are likely to develop HSR. The interaction of abacavir or
its metabolite with the major histocompatibility complex (MHC) class I may lead to a
CD8+ T-cell-mediated cell death. 58,59 Of those with positive status, more than 70% of
patients develop HSR. The prevalence of the HLA-B*5701 allele is the highest in white
populations (5–8%). 56,60–62 In African American, Asian, and Hispanic populations, the
prevalence is 0.26–3.6%. 61–64
Clinical Relevance
Dosing and efficacy of abacavir have not been shown to be affected by HLA-B*5701.
The clinical utility of HLA-B*5701 testing for abacavir has been demonstrated from
several prospective clinical studies. In the PREDICT-1 study, the incidence of confirmed
abacavir-associated HSR was 2.7% in the control group versus 0% in the HLA-
B*5701 screened group (p < 0.001). 65 In the retrospective, case–control SHAPE study,
47 of 199 white and black patients had suspected HSR cases, with confirmation from
a skin patch test. In this study, HLA-B*5701 screening accurately predicted 100% of
abacavir-associated HSR cases. It should be noted that skin patch testing identifies
patients who had an immunologically mediated HSR to abacavir. However, it is only
useful for confirmation of suspected HSR cases, and it does not work in those without
previous exposure to abacavir. 66 In the ARIES study, HLA-B*5701-negative patients
had less than 1% clinically suspected abacavir-induced HSR, and none had positive skin
patch tests at 30 weeks. 67
Testing Availability and Recommendations
Abacavir-induced HSR has been associated with the presence of the MHC class I
allele HLA-B*5701. A screening test for the HLA-B*5701 allele may allow clinicians
to identify patients who are at risk of developing an HSR to abacavir. Due to the
severity of the HSR and its potential impact on overall antiretroviral regimens, the
HLA-B*5701 screening test may help minimize potential abacavir toxicity and thus
optimize antiretroviral therapy. To test the HLA-B*5701 allele, a blood or saliva sample
specimen is collected. The genetic sequences coding for the HLA-B*5701 are probed
and reported as positive if the allele is present, or negative if the allele is absent.