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Published: November 2008Print Record of Viewing
An FDA safety alert reported studies linking potentially fatal hypersensitivity reactions with abacavir, an HIV-antiretroviral medication, to a specific HLA-B allele (HLA-B*5701). Testing patients for this allele, prior to receiving abacavir, is now recommended. Dr. O’Kane and Dr. Yao discuss what this means for you and your patients.
Presenter: Dennis J. O'Kane, PhD of the Division of Clinical Biochemistry & Immunology at Mayo Clinic
Presenter: Joseph D. Yao, MD of the Division of Clinical Microbiology at Mayo Clinic
Welcome to Mayo Medical Laboratories’ Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.
Our presenters for this program are Dr. Dennis O’Kane and Dr. Joseph Yao.
Dr. O’Kane is co-director of the nucleotide polymorphism laboratory in the division of clinical biochemistry and immunology. Dr. Yao is from the Division of Clinical Microbiology at Mayo Clinic.
Dr. O’Kane and Dr. Yao will be discussing the recent FDA safety alert linking potentially fatal hypersensitivity reactions with abacavir, a nucleoside RT inhibitor of Human Immunodeficiency Virus to a specific HLA-B allele, HLA-B*5701, and what this means for patient care.
Highly Active Anti Therapy has been available for the last 15 years, and there are three groups of drugs that are effective against HIV virus. The earliest group of drugs that became commercially available are the nucleoside reverse transcriptase inhibitors. There are six of them listed here.
Then, there are the nonnucleoside reverse transcriptase inhibitors, and three of these are commercially available and FDA-approved in the United States.
Finally, the protease inhibitors, as illustrated here.
There are two other groups of retroviral therapy that have been available commercially in the last two years. The integrase inhibitors as well as the HIV entry co-receptor antagonists, but those have not made it into the mainstream of combination therapy until recently.
The definition of HAART is defined by a combination of at least two of these drug combinations and the nonnucleoside can be combined with one protease or one nucleoside reverse transcriptase inhibitor or combined with two protease inhibitors.
Abacavir is a nucleoside reverse transcriptase inhibiting of the human immunodeficiency virus. It is used in HAART therapy in combination with other anti-HIV drugs. It is marketed in the United States as Ziagen as a single drug, or as a fixed combination with other drugs and marketed as Epzicon and Trizivir.
In July 2008, the FDA alert came about on a review of studies linking potentially fatal hypersensitivity reactions with abacavir in relations to a specific HLA-B allele (HLA-B*5701). Testing of HIV infected patients for this allele is recommended prior to prescribing Abacavir. This information is now added to the box warning and product label for this drug.
Abacavir hypersensitivity reaction (HSR) is a serious, sometimes fatal, multi-organ syndrome. It is characterized by at least 2 or more of the clinical signs listed here, including fever, rash, gastrointestinal symptoms, respiratory symptoms or other constitutional symptoms such as fever, malaise, or fatigue.
Abacavir hypersensitivity reaction is significantly more common in patients with the specific human leukocyte antigen (HLA) allele, HLAB*5701.
The HLA genes are located on the short arm of chromosome 6, and these genes encode for cell surface-expressed protein.
Class I are expressed on most nucleated cells. These are encoded by HLA-A, HLA-B, and HLA-C genes. Class II are found on antigen-presenting cells. These are encoded by HLA-DR, HLA-DQ, and HLA-DP genes.
The Class I HLA proteins (including HLA-B) present peptides to CD8+ T lymphocytes. This may elicit an immune response. HLA-B is a single gene, but generates many protein antigens. However, more than 500 allelic variants are identified by molecular methods. Not all these allelic variants cause a change in the amino acid sequence of the HLA-B antigen, and approximately 50 HLA-B protein antigens encoded by the HLA-B allelic variants and these are identified serologically.
The naming convention can be confusing. HLA-B is the name of the gene located on chromosome 6. B57 indicates a group of protein antigens with different amino acid substitutions, encoded by the HLA-B alleles, which are detected immunologically. The asterisk (*) indicates it is nucleic acid - an allele - and not a protein, which is an antigen. The 01 indicates a specific allele with a specific DNA sequence. There are 16 HAL-B*5701 alleles with amino acid changes that have been found at this time. Many of these are rare, for example HLA-B*5708 found in 1 in 25,000 patients.
This is a synopsis of the HLA-B gene. As indicated, it was found on short arm of chromosome 6. The reddish rectangle indicates the centromere of the chromosome. So, HLA-B genes and the other HLA alleles are found on the short arm of chromosome 6.
What is indicated here is the genomic DNA sequence and the orientation of the various HLA genes. A is closer to the telomere on the left hand side than C or B or the DR, DQ, and DP alleles. For convenience, the HLA-B gene is shown oriented from left to right with exon 1, exon 2 and the other coding exons indicated in the blue rectangles. Most of the changes that affect the formation of different protein antigens are encoded in exon 2 or exon 3.
What’s shown underneath the blue rectangle is the messenger RNA for the HLA-B system and underneath that is a spec sequence of ribonucleotides in the message for this particular gene encoding part of exon 2 and exon 3. The reference sequence for the HLA alleles for the B gene is shown on the top and underneath are individual nucleotide changes in the mRNA for the 5701 allele.
Beneath that are the amino acid sequences. For the reference sequence, we have a full sequence indicated. Underneath that are the B57 antigen changes where the amino acids are substituted, as indicated by the red lettering. So, there are several changes from the reference sequence that makes an allele a 57 antigen.
The Class I HLA antigens are frequently typed immunologically prior to organ and bone marrow transplantation and there are various methods that are used. Some low to moderate methods do not give all details necessary to ascertain which patient has the HLA-B*5701 allele.
Some of these methods include flow cytometry, since HLA genes are expressed on the surface of most nucleated cells. Immunophenotyping with strip devices or hybridization of the DNA with allele-specific probes are two other methods used.
Increased resolution can be obtained using other methodologies such as sequence-specific PCR which is specifically dependent upon precise complementarity of the PCR primer with the target DNA sequence or by bidirectional DNA sequencing, which is the most accurate but can be quite costly to perform.
An alternative approach is to perform screening using low to moderate resolution techniques to screen all patients and then to confirm positives with high-resolution sequencing.
The HLA-B*5701 allele is involved in hypersensitivity reaction with abacavir in 5-8% of patients who initiate therapy. Prevalence of the HLA-B*5701 allele varies among racial groups; however, the point is it is present in all racial and ethnic groups that have been tested to some extent. Consequently, all patients who are going to be receiving this drug should be tested for this specific allele. And there are very high odds ratio for abacavir hypersensitivity reaction when the patient carries the HLA-B*5701 allele.
However, there is a significantly lower odds ratio, down to 0.03, for abacavir hypersensitivity reactions by prospective screening for HLA-B*5701 allele in immunologically-confirmed hypersensitivity reactions.
Prospective screening and exclusion of patients with the HLAB*5701allele reduces the incidence of abacavir hypersensitivity reactions.
In patients who have clinically-suspected hypersensitivity reaction, the sensitivity approximately 46% and the specificity is about 98%. The negative predictive value is exceedingly high and is about 100%, where the absence of HLA-B*5701 correlates with absence of abacavir hypersensitivity reaction. The positive predictive value is approximately 61% and this correlates with individuals with the HLA-B*5701 allele who had a suspected hypersensitivity reaction with abacavir.
Immunologically-confirmed hypersensitivity reactions, however, show higher sensitivity and specificity. The negative predictive value is still 100% and the positive predictive value is about 48% with individuals who have the alleles and had a confirmed hypersensitivity reaction.
There are problems in that these may not actually be related to HLA-B*5701. Some minor or moderate symptoms may be due to other causes. Furthermore, not all assays are 100% specific. Other non-5701 alleles that are rare are sometimes reported in only a single individual, but may be detected by the assays. High-resolution bidirectional DNA sequencing is the most accurate test, but it’s also the most expensive test as well.
Now for patients who are about to receive abacavir, this is a suggested algorithm for approaching the prob. First one must determine is HLA-B*5701 testing is available. If it is not avail or if the clinician has no access to test, then provider should review risk factors with patient and start abacavir therapy and monitor for the occurrence of hypersensitivity reaction looking for signs and symptoms consistent with syndrome.
However, if testing is available, then the status of this allele should be determined with lab testing. If negative, the provider should proceed with initiating abacavir therapy. If the allele is present, then abacavir therapy should be avoided.
The abacavir hypersensitivity reaction symptoms can be classified in one of five groups as seen in the top box. If there are two or more symptoms from two groups within six weeks of starting abacavir therapy, then abacavir should be withheld and the provider should offer supportive therapy as clinical necessary.
Skin patch testing, which is actually phenotypic test for abacavir hypersensitivity reaction could be done. If the skin patch test is positive, the patient should not receive abacavir therapy again. However, if the skin patch test is negative, then re-challenge the patient with abacavir therapy in carefully observed hosp setting.
On the other hand, if the patient has only one or no symptoms within six weeks of starting abacavir, then treatment can be continued, but the patient should still be monitored closely for possible delayed occurrence of hypersensitivity reaction.
These are the following recommendations for providers who care for patients with HIV infection and providing abacavir therapy. Prior to starting, all patients should be screened for the HLA-B *5701 allele to reduce risk of hypersensitivity reaction to this drug.
Screening for this allele is recommended prior to reinitiation, as these would be patients who have had some sort of hypersensitivity reaction, but it is not known whether it is due to abacavir. So if upon restarting abacavir therapy, there is a hypersensitivity reaction, then these patients should avoid abacavir permanently.
Finally, if a patient is HLA-B*5701-positive, abacavir treatment regimens are not recommended and should be considered “only under exceptional circumstances when the potential benefit outweighs the risk.”
For those patients who are HLA-B*5701 negative by laboratory testing, there is still a residual risk for developing abacavir hypersensitivity reaction. Because, as you remember from previous slides, the negative predictive value is not 100% so these HLA-B*5701-negative patients should still be monitored for signs and symptoms of a possible hypersensitivity reaction to abacavir.
If the patient becomes seriously ill and a hypersensitivity reaction cannot be ruled out, discontinue abacavir therapy permanently, regardless of HLA-B*5701 status.
In addition, prescribers should not restart abacavir or any abacavir-containing drug combination following occurrence of abacavir hypersensitivity reaction. This is because severe symptoms can occur within hours of reinitiating and can result in life-threatening hypotension and death.
For the patients, providers should inform them that they are at greater risk for serious allergic reactions when first starting treatment with abacavir or with combined therapy that contains abacavir.
Patients should be aware that HLA-B*5701 status, which is a risk-factor for these hypersensitivity reactions, should be determined prior to starting abacavir therapy.
Patients should also know that these they are at high risk for hypersensitivity reaction if their laboratory tests are positive.
Providers can also inform the patients that they are at lower risk of a serious hypersensitivity reaction when taking abacavir, however, hypersensitivity reaction can still occur because a negative test result is not 100% predictive.
Finally, patients with unknown HLA-B*5701 status should be tested prior to reinitiating abacavir treatment, even if they tolerated abacavir previously.
At Mayo Medical Laboratories, the HLA-B*5701 allele typing is done by a genotyping method as described by Dr. O’Kane under the unit code 89346 with the published name HLA-B*5701 Genotype, Abacavir Hypersensitivity.
This assay is useful for predicting the likelihood of hypersensitivity reactions to abacavir in HIV-infected patients, based on the presence of the HLA-B*5701 allele and it is therefore useful to exclude these patients if they’re positive for this allele.
On this page, we're providing references that you may find helpful in getting more insight and information on the assoc of HLA-B*5701 with hypersensitivity reaction to abacavir.