Coverage Policy Manual
Policy #: 2012069
Category: Laboratory
Initiated: December 2012
Last Review: November 2023
  Genetic Test: Allopurinol Sensitivity (HLA-B*5801)

Description:
Allopurinol, frequently used for the treatment of gout and hyperuricemia is a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnsons syndrome (SJS) and toxic epidermal necrolysis (TEN).  Although SCARs are rare, they can be life threatening with significant mortality rates.
 
A strong association between SCAR and HLA-B*5801 has been observed in the Han Chinese and Thai populations (Tassaneeyakul, 2009; Cao, 2012). Genotyping has been used to select alternative treatments in those individuals with presence of the HLA-B*5801 allele.
 
 

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
HLA-B*5801 allele testing for sensitivity to allopurinol meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following individuals:
 
      • Korean individuals with stage 3 or worse chronic kidney disease (CKD); OR
      • Individuals of Han Chinese or Thai descent regardless of their renal function.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
HLA-B*5801 allele testing for sensitivity to allopurinol for any indication not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, HLA-B*5801 allele testing for sensitivity to allopurinol for any indication not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
Allopurinol hypersensitivity reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and other systemic disease has a reported mortality rate of about 20-25% (Khanna, 2012). Several studies have linked HLA-B*5801 allele with allopurinol-induced severe cutaneous adverse drug reactions in the Korean, Chinese Han and Thai populations (Tassaneeyakul, 2009). Jung, 2011; Hung, 2005; Cao, 2012).
 
In 2005, Hung et al reported results of case-control association study where genotyping was performed in 51 patients with allopurinol –induced severe cutaneous adverse reactions (SCAR) and 228 control individuals (135 allopurinol tolerant and 93 healthy subjects).  The HLA-B*5801 allele was present in all 51 patients with allopurinol-induced SCAR and only 20 of the 135 tolerant patients (Hung, 2012).
 
A strong association has also been reported between the presence of HLA-B*5801 allele and allopurinol-induced SJS in individuals of Thai descent. Tassaneeyakul and colleagues enrolled 27 patients with allopurinol-induced SJS/TEN and 54 allopurinol-tolerant patients (Tassaneeyakul, 2009). One hundred percent of the patients with allopurinol-induced SJS/TEN were positive for the HLA-B*5801 allele (Tassaneeyakul, 2009).
 
In 2012, Jung and colleagues conducted a retrospective review of the medical records of patients with chronic renal insufficiency taking allopurinol (Jung, 2012). Out of the 448 patients with chronic renal insufficiency, nine patients were diagnosed with SCARs. All patients (100%) that were diagnosed with SCARs were positive for the HLA-B*58 allele, whereas only 9.5% of allopurinol patients were positive for the allele (Jung, 2012).
 
In 2012, the American College of Rheumatology (ACR) published guidelines for the management of Gout (Kanna, 2012). The guideline includes recommendations specific to allopurinol dosing and pharmacogenetics which include HLA-B*5801 prior to initiation of allopurinol for the following high risk populations:
 
    • Korean individuals with stage 3 or worse chronic kidney disease; OR
    • Individuals of Han Chinese or Thai descent regardless of their renal function.
 
The panel recommended that the HLA-B*5801 testing be performed by rapid polymerase chain reaction (PCR) (Kanna, 2012).
 
Based on the findings of clinical studies (Tassaneeyakul, 2009; Jung, 2011; Hung, 2005; Cao, 2012) and the 2012 ACR Guidelines (Kanna, 2012), genetic testing for HLA-B*5801 in high risk patients (i.e., Koreans with stage 3 CKD or worse, Han Chinese and Thai) prior to initiation of allopurinol meets primary coverage criteria.
 
2013 Update
A search of the MEDLINE database through November 2013 did not reveal any new literature that would prompt a change in the coverage statement.
  
2014 Update
A literature search conducted using the MEDLINE database through October 2014 did not reveal any new information that would prompt a change in the coverage statement.  
 
2015 Update
A literature search conducted through October 2015 did not reveal any new information that would prompt a change in the coverage statement.
 
2016 Update
A literature search conducted through October 2016 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 October 2017 did not reveal any new information that would prompt a change in the coverage statement.
   
2018 Update
A literature search was conducted through October 2018.  There was no new information 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 October 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was 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 October 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 October 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 October 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: Hung SI, Chung WH, Liou LB, et al.(2005) HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4134-9. Epub 2005 Mar

Khanna D., Fitzgerald J.D., Khanna P.P., et al.(2012) 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012 Oct;64(10):1431-46.

Somkrua R., Eickman E.E., Saokaew S., et al.(2011) Association of HLA-B*5801 allele and allopurinol-induced stevens johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. BMC Medical Genetics 2011, 12:118. Accessed at http://www.biomedcentral.com/1471-2350/12/118

Tassaneeyakul W, Jantararoungtong T, Chen P, et al.(2009) Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics. 2009 Sep;19(9):704-9.


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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