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HLA B 5701 Testing


HLA B 5701 Testing

Article Author:
Brian Gilani
Article Editor:
Deepa Budh
Updated:
7/26/2020 11:26:52 AM
For CME on this topic:
HLA B 5701 Testing CME
PubMed Link:
HLA B 5701 Testing

Introduction

Human immunodeficiency virus (HIV) is a viral infection that targets the body’s immune system--specifically CD4+ T cells. The disease is transmitted through bodily fluids but can remain undetected in its host for years, causing a diverse array of complications to the sufferer. During the progression of HIV infection, a patient’s CD4 cell count will decrease as the lymphocytes are hijacked and destroyed to reproduce HIV. Individuals that do not receive treatment can develop AIDS once their CD4 cell count drops below 200, which indicates the individual is highly susceptible to opportunistic infection. Patients that develop untreated AIDS have a 1 to 2 years prognosis of survival.[1]

Due to the loci of infection, the management of the virus uses a multifaceted approach. The core of HIV treatment is antiretroviral therapy (ART). In a majority of patients, ART includes two nucleoside reverse transcriptase inhibitors (NRTIs) and an integrase strand transfer inhibitor (InSTI).[2] These regimens seek to interrupt viral replication and slow the progression of the infection. Within the class of NRTIs is abacavir. Abacavir has shown to cause a hypersensitive response in five to eight percent of patients treated. A hypersensitive reaction can be life-threatening upon rechallenge to the system. Therefore, understanding the mechanism and predictive power of the HLA-B 5701 allele concerning hypersensitive reactions is critical in shaping the best clinical practices.[3][4]

Specimen Collection

Specimen collection uses whole blood(WB) and buccal mucosa swabs. The volume of the sample/specimen should be 7 mL in WB-Lavender-top (EDTA) tube and four buccal swabs (in a sealed buccal swab envelop kit). It is advisable to maintain and dry the specimens at room temperature. Precautions are necessary regarding the prevention of hemolysis or dried specimens that interfere with appropriate test results.

Procedures

After establishing a link between the HLA B 5701 allele and abacavir, monitoring for the allele and hypersensitive response became routine in antiretroviral therapy, accomplished through genetic screening. Testing for HLA B 5701 most commonly uses a blood or saliva sample for sequence-based genotyping using a polymerase chain reaction.[3] Following these tests, the clinician will know if the patient is positive for the HLA B 5701 allele and be able to alter the treatment accordingly.

For patients with the HLA B 5701 allele, safely and conclusively diagnosing hypersensitivity is another necessary step in determining drug efficacy. To confirm hypersensitivity, an epicutaneous patch test is administered after the patient has had exposure to abacavir. A skin patch must take place after the immune system has been exposed to the drug’s effects because a rechallenge will produce a measurable response. Skin patch testing uses concentrations of 1% and 10% abacavir in petrolatum along with control without abacavir. These patches can then be read at 24 and 48 hours after application. A positive hypersensitive response is when there is a palpable cutaneous response on the skin surface where abacavir was introduced.[5][6][7]

Indications

Patients identified with HIV should be screened for HLA B 5701 when preparing an antiretroviral therapy drug regimen, especially when considering abacavir. 

Normal and Critical Findings

Screening for the presence of the HLA B 5701 allele should always be conducted to avoid possible morbidity due to allergic reactions. Due to the implications of positive results for the HLA B 5701 allele, using abacavir in treatment is contraindicated. Instead, physicians should substitute with a different NRTI in the patient's therapeutic regimen. It bears mentioning that in rare cases where HLA B 5701 testing is not available due to geographically low prevalence of the allele, physicians may prescribe abacavir under close observation for the first six weeks, although the median time of onset typically occurs at 1 to 2 weeks.[8] If the patient is negative for the allele, physicians can safely resume with abacavir as a component of the patient's regimen.

Interfering Factors

In studies of abacavir hypersensitivity reaction or AHR, researchers found that a significant portion of hypersensitive diagnoses were false positives using epicutaneous patch testing. HLA B 5701 screening has shown to have a 100% negative predictive value.[9] Interestingly, although all patients that develop hypersensitivity have the HLA B 5701 allele, not all individuals with that genotype develop hypersensitivity. Mouse models have supported the hypothesis that CD4 cells play a role in building tolerance for the altered antigen-presenting complex through cytotoxic lymphocyte driven hypersensitive response.[10][11]

In the diagnosis of hypersensitivity in patients, clinicians must use patch testing to confirm their diagnosis. In blind comparative trial regimens, two to seven percent of patients were diagnosed with hypersensitivity without receiving abacavir.[12] This discrepancy in true positive hypersensitivity recognition is due to the symptoms of hypersensitivity being nonspecific and difficult to distinguish from other ailments that could accompany the introduction of a new drug regimen.

Complications

Hypersensitivity can manifest as a variety of symptoms. The most common of AHR symptoms include fever, chills, rash, gastrointestinal and respiratory symptoms. Patch testing is often used as a confirmation of hypersensitivity and will cause a palpable cutaneous response on the skin.[13]

Clinical Significance

Abacavir, as an NRTI, competes with deoxynucleotides in host cells to prevent the creation of double-stranded viral DNA. When preventing this viral double-stranded DNA from being encoded, the virus is unable to be reproduced in the host CD4 lymphocytes. Hypersensitivity can arise when individuals with antigen-presenting complexes linked to HLA B 5701 perform direct noncovalent bonding with abacavir. Once bonded, the surface complex is altered and is then recognized as foreign by cytotoxic lymphocytes. This interaction results in the release of inflammatory cytokines that facilitate the hypersensitive response.[5]

Due to the severity of AHR, it is important to conduct screenings for the HLA B 5701 allele to avoid a hypersensitive response in patients predisposed to this outcome. In selecting a regimen, physicians must take into account the patient’s HLA B 5701 status. The recommendation is that patients receive an alternative NRTI to abacavir if they have the HLA B 5701 allele to avoid the possibility of a hypersensitive response.

Along with a patient’s genetic profile for the HLA B allele, it is also vital for the physician to review the patient’s medication history with abacavir. Since rechallenging the immune system after a hypersensitive response can produce extreme and life-threatening symptoms, there should be additional caution when considering abacavir in patients who may have had an allergic reaction previously. Skin patch testing can also be a consideration in these cases since it is used exclusively in patients that have already taken abacavir and serve as a localized challenge instead of a systematic reintroduction.

If clinicians observe these protocols and recommendations, physicians and patients will be capable of making an informed selection of the components of their antiretroviral therapy. For most, abacavir is very effective in concert with an additional NRTI and an InSTI, but for a small percentage of genetically predisposed individuals, abacavir can result in a harmful hypersensitive reaction.


References

[1] Simon V,Ho DD,Abdool Karim Q, HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet (London, England). 2006 Aug 5;     [PubMed PMID: 16890836]
[2] Günthard HF,Saag MS,Benson CA,del Rio C,Eron JJ,Gallant JE,Hoy JF,Mugavero MJ,Sax PE,Thompson MA,Gandhi RT,Landovitz RJ,Smith DM,Jacobsen DM,Volberding PA, Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2016 Jul 12;     [PubMed PMID: 27404187]
[3] Ma JD,Lee KC,Kuo GM, HLA-B*5701 testing to predict abacavir hypersensitivity. PLoS currents. 2010 Dec 7;     [PubMed PMID: 21151380]
[4] Shapiro M,Ward KM,Stern JJ, A near-fatal hypersensitivity reaction to abacavir: case report and literature review. The AIDS reader. 2001 Apr;     [PubMed PMID: 11392679]
[5] Illing PT,Vivian JP,Dudek NL,Kostenko L,Chen Z,Bharadwaj M,Miles JJ,Kjer-Nielsen L,Gras S,Williamson NA,Burrows SR,Purcell AW,Rossjohn J,McCluskey J, Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature. 2012 Jun 28;     [PubMed PMID: 22722860]
[6] Phillips EJ,Wong GA,Kaul R,Shahabi K,Nolan DA,Knowles SR,Martin AM,Mallal SA,Shear NH, Clinical and immunogenetic correlates of abacavir hypersensitivity. AIDS (London, England). 2005 Jun 10;     [PubMed PMID: 15905681]
[7] Shear NH,Milpied B,Bruynzeel DP,Phillips EJ, A review of drug patch testing and implications for HIV clinicians. AIDS (London, England). 2008 May 31;     [PubMed PMID: 18520343]
[8] Martin MA,Kroetz DL, Abacavir pharmacogenetics--from initial reports to standard of care. Pharmacotherapy. 2013 Jul;     [PubMed PMID: 23649914]
[9] Saag M,Balu R,Phillips E,Brachman P,Martorell C,Burman W,Stancil B,Mosteller M,Brothers C,Wannamaker P,Hughes A,Sutherland-Phillips D,Mallal S,Shaefer M, High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2008 Apr 1;     [PubMed PMID: 18444831]
[10] Phillips EJ,Mallal SA, Active suppression rather than ignorance: tolerance to abacavir-induced HLA-B*57:01 peptide repertoire alteration. The Journal of clinical investigation. 2018 Jul 2;     [PubMed PMID: 29781810]
[11] Cardone M,Garcia K,Tilahun ME,Boyd LF,Gebreyohannes S,Yano M,Roderiquez G,Akue AD,Juengst L,Mattson E,Ananthula S,Natarajan K,Puig M,Margulies DH,Norcross MA, A transgenic mouse model for HLA-B*57:01-linked abacavir drug tolerance and reactivity. The Journal of clinical investigation. 2018 Jul 2;     [PubMed PMID: 29782330]
[12] Mallal S,Phillips E,Carosi G,Molina JM,Workman C,Tomazic J,Jägel-Guedes E,Rugina S,Kozyrev O,Cid JF,Hay P,Nolan D,Hughes S,Hughes A,Ryan S,Fitch N,Thorborn D,Benbow A, HLA-B*5701 screening for hypersensitivity to abacavir. The New England journal of medicine. 2008 Feb 7;     [PubMed PMID: 18256392]
[13] Hughes CA,Foisy MM,Dewhurst N,Higgins N,Robinson L,Kelly DV,Lechelt KE, Abacavir hypersensitivity reaction: an update. The Annals of pharmacotherapy. 2008 Mar;     [PubMed PMID: 18303141]