Coverage Policy Manual
Policy #: 2011009
Category: Laboratory
Initiated: May 2011
Last Review: June 2023
  Genetic Test: HLA-B*5701 Testing for Abacavir Hypersensitivity Reaction
Description:
Abacavir is an oral nucleoside reverse transcriptase inhibitor that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of human immunodeficiency virus (HIV)-1 infection.  
 
Abacavir is associated with a hypersensitivity reaction that occurs in approximately 5—10% of patients. This hypersensitivity reaction, characterized by fever, skin rash, fatigue, gastrointestinal symptoms, and, sometimes, respiratory symptoms, can be life-threatening. The majority of abacavir hypersensitivity reactions occur n the first 6 weeks following abacavir initiation. When a hypersensitivity reaction cannot be ruled out, abacavir treatment should be permanently discontinued.  On July 18, 2008, the FDA approved changes to the package insert for abacavir sulfate, highlighting information about the association of the HLA-B*5701 allele and hypersensitivity reactions caused by abacavir-containing treatments. The label change recommends testing patients for the HLA-B*5701 allele prior to initiation or reinitiating abacavir containing treatment.  
 
The commercially available HLA-B*5701 assays use polymerase chain reaction (PCR) followed by sequence oligonucleotide probes to determine the presence of the HLA-B*5701 allele. The HLA-B*5701 test is performed on whole blood or a buccal swab.
 
 
 
Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for HLA-B*5701 for hypersensitivity reactions in patients with HIV prior to initiation or reinitiation with treatments containing abacavir meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for HLA-B*5701 in patients who are currently taking abacavir and begin experiencing symptoms of hypersensitivity reaction does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, testing for HLA-B*5701 in patients who are currently taking abacavir and begin experiencing symptoms of hypersensitivity reaction is considered investigational.  Investigational services are specific contract exclusions.  
Rationale:
This policy was developed as a result of the FDA approved changes to the package insert for Ziagen (abacavir sulfate) which recommends testing for patients for the HLA-B*5701 allele prior to initiating or reinitiating abacavir therapy.
 
A few studies have reported the analytical validity of HLA-B*5701 testing. Hammond and colleagues used an HLA-B*5701 assay that involved allele-specific PCR AS-PCR) with melting curve analysis.  The accuracy of the AS-PCR assay for detecting HLA-B*5701 in 96 samples was reported as 100% for both sensitivity and specificity (Hammond, 2007). Martin and colleagues describe a method of identifying HLA-B*5701 using PCR sequence-specific primers.  The authors note that the PCR sequence-specific primers HLA-B*5701 could distinguish between the HLA subtypes of *5701, *5702, *5703 and *5704 consistently and was validated. However, sensitivity and specificity were not reported.
 
Saag et al conducted a study to assess the sensitivity of detection of the HLA-B*5701 allele as a marker of abacavir hypersensitivity reactions (HSR) in both white (N=130) and African-American (N=69) patients. Patients (N=199) with a skin patch test confirmed diagnosis of abacavir HSR were tested for the presence of HLA-B*5701. The author reports a sensitivity of 100% for identifying African-Americans and whites with patch test-confirmed hypersensitivity reaction.
 
The PREDICT-1 study randomly assigned 1956 patients to undergo HLA-B*5701 testing with exclusion of HLA-B*5701 positive patients from abacavir treatment or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 testing (Mallal, 2008). The prevalence of HLA-B*5701 was 5.6%. The authors report a negative predictive value of 100% and a positive predictive value of 47.9%.
 
A large, multi-center open label study (Young, 2008) confirmed the results of the PREDICT-1 study. The study excluded HLA-B*5701 –positive patients and determined the rate of abacavir hypersensitivity reaction among HLA-B*5701 negative patients treated with abacavir/lamivudine, atazanavir, and ritonavir.  The study enrolled 517 HLA-B*5701 negative patients who began abacavir treatment. During the first 30 weeks of treatment, only four out of the 517 treated patients were diagnosed with clinically suspected abacavir hypersensitivity reaction.  However, all four patients had negative skin patch test results.  
 
The Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents (DHHS Panel) recommends HLA-B*5701 testing prior to patients being treated with any abacavir-containing regimen.  The panel also recommends that HLA-B*5701 testing should not be a substitute for clinical judgment because a negative result does not absolutely rule out the possibility of some form of abacavir hypersensitivity reaction.  
 
Based on the excellent negative predictive value of the HLA-B*5701 in a large randomized, controlled study and the FDA approved label revision recommending this testing, HLA-B*5701 testing meets primary coverage criteria in HIV patients prior to initiation or reinitiation of abacavir testing.  However, since there have been rare cases of suspected hypersensitivity reaction in patients lacking the HLA-B*5701 allele (Calza, 2009), testing to confirm clinically suspected hypersensitivity reaction in patients already receiving abacavir does not meet primary coverage criteria.
 
2012 Update
A literature search was conducted through May 2012.  There was no new literature identified that would prompt a change in the coverage statement.
 
2014 Update
A literature search conducted using the MEDLINE database through May 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted using the MEDLINE database through May 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2018. No new literature was identified that would prompt a change in the coverage statement.       
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through May 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
81381HLA Class I typing, high resolution (ie, alleles or allele groups); one allele or allele group (eg, B*57:01P), each
References: Calza L, Rosseti N, Biagetti C, et al.(2009) Abacavir-induced reaction with fever and severe skin rash in a patient tested human leukocyte antigen-B*5701 negative. Int J STD AIDS. 2009;20:276-277.

Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents (DHHS Panel).(2008) Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. AIDSinfo [website]. Updated January 29, 2008. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Last accessed May 6, 2010.

Hammond E, Manmotte C, Nolan D et al.(2007) HLA-B*5701 typing: evaluation of an allele-specific polymerase chain reaction melting assay. Tissue Antigens. 2007;70(1):58-61.

Mallal S, Phillips E, Carosi G, et al.(2008) Hla-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358:568-579.

Saag M, Balu R, Phillips E, et al.(2008) High sensitivity of human leukocyte antigen-B*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clin Infect Dis. 2008;46:1111-1118.

Young B, Squires K, Patel P, et al.(2008) First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America. AIDS 2008, 22:1673-1681.

Ziagen® (abacavir sulfate) Tablets and Oral Soultion [package insert]. Research Triangle Park, NC: GlaxoSmithkline;
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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