Abacavir and HLA-B*5701

Updated: Feb 13, 2015
  • Author: Ali Torkamani, PhD; Chief Editor: Karl S Roth, MD  more...
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Overview

Overview

Abacavir is a nucleoside reverse transcriptase inhibitor used in conjunction with other antiretroviral agents in the treatment of HIV infection. [1, 2] HIV, a positive single-stranded RNA virus, undergoes reverse transcription to produce double-stranded viral DNA, which is subsequently incorporated into the host genome and used to produce viral progeny using the host's cellular machinery. Abacavir competes with naturally occurring deoxynucleotides during the viral reverse transcription process. When incorporated into the growing viral DNA strand, abacavir blocks further strand elongation, leading to a premature halt in viral DNA synthesis and chain termination.

Abacavir is generally well tolerated but can cause hypersensitivity in 5% to 8% of patients during the first 6 weeks of treatment. [3] Symptoms include fever, rash, constitutional symptoms, gastrointestinal tract symptoms, and respiratory symptoms. Symptoms worsen with continued usage and can be potentially life threatening if the patient is rechallenged after discontinuation. [3]

Hypersensitivity to abacavir is immunologically mediated, driven by conventional MHC-I antigen presentation and activation of HLA-B*5701. [4, 5, 6, 7] Activation of HLA-B*5701 restricted CD8+ T cells results in the secretion of the inflammatory mediators TNF-alpha and IFN-gamma and induces the delayed-type hypersensitivity reaction. [4] It is thought that a derivative of the abacavir prodrug binds to an antigen-presenting cleft unique to HLA-B*5701, which explains why the drug does not cause a similar hypersensitivity syndrome in carriers of other HLA-B alleles and why compounds similar to abacavir do not react with HLA-B*5701. [4]

The HLA-B*5701 allele occurs at approximately 5% frequency in European populations, 1% in Asian populations, and less than 1% in African populations.

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Clinical Implications and Genetic Testing

In immunologically confirmed hypersensitivity, HLA-B*5701 genotyping is associated with a negative predictive value of nearly 100% and a positive predictive value of approximately 50%. [8] That is, patients without the allele are highly unlikely to develop an immunological hypersensitivity to abacavir, but only about half of those with the allele will develop such a reaction.

Thus, although the carriage rate of the HLA-B*5701 allele is low, stratification of patients for abacavir treatment based on HLA-B*5701 genotyping could virtually eliminate immunologically confirmed hypersensitivity and appears to be a cost-effective healthcare practice. [8, 9]

Screening for HLA-B*5701 prior to initiation of abacavir therapy is widely recommended for abacavir-naive individuals. [10, 11, 12] However, its necessity in low-risk populations, such as the Han-Chinese in Hong Kong, has been questioned. [13]

Abacavir’s FDA-approved prescribing information includes a black box warning about the risk of hypersensitivity in carriers of the allele and a recommendation about screening. HLA-B*5701–positive individuals should not be prescribed abacavir. That being said, a negative HLA-B*5701 test does not preclude the development of a nonimmunologic hypersensitivity reaction to abacavir or of a clinical hypersensitivity reaction to another antiretroviral agent that may be given along with abacavir. [8] Genotyping should not substitute for clinical vigilance but can greatly reduce the incidence of abacavir hypersensitivity by identifying patients at high risk before they are treated.

Better virological but not immunological responses to combination antiretroviral therapy (cART) have been shown in HLA-B*5701-positive patients on nonabacavir regimens. In a British study, HLA-B*5701-positive patients were more likely to achieve viral suppression than negative patients on a nonabacavir regimen [hazard ratio=1.29, 95% confidence interval, CI (1.15-1.54)] and less likely to experience viral rebound [hazard ratio=0.61, 95% CI (0.37-0.99)]. [14]

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