The strength of therapeutic recommendations (Strong, Moderate, Optional) is defined at the end of the "Major Recommendations" field.
Genetic Test Interpretation
The assignment of the likely human leukocyte antigen B (HLA-B) phenotype, based on allele diplotypes, is summarized in Table 1 below.
Table 1. Assignment of Likely HLA-B Phenotypes Based on Genotypes
||Examples of Diplotypes
|Very low risk of hypersensitivity (constitutes ~94%a of patients)
||Absence of *57:01 alleles (reported as "negative" on a genotyping test)
|High risk of hypersensitivity (~6% of patients)
||Presence of at least one *57:01 allele (reported as "positive" on a genotyping test)
aSee Supplementary Data (see the "Availability of Companion Documents" field) for estimates of genotype frequencies among different ethnic/geographic groups.
b*X = any HLA-B genotype other than *57:01.
The guideline authors agree with others that HLA-B*57:01 screening should be performed in all abacavir-naive individuals before initiation of abacavir-containing therapy (see the table below); this is consistent with the recommendations of the U.S. Food and Drug Administration, the U.S. Department of Health and Human Services, and the European Medicines Agency. In abacavir-naive individuals who are HLA-B*57:01-positive, abacavir is not recommended and should be considered only under exceptional circumstances when the potential benefit, based on resistance patterns and treatment history, outweighs the risk. HLA-B*57:01 genotyping is widely available in the developed world and is considered the standard of care prior to initiating abacavir. Where HLA-B*57:01 genotyping is not clinically available (such as in resource-limited settings), some have advocated initiating abacavir, provided there is appropriate clinical monitoring and patient counseling about the signs and symptoms of hypersensitivity reaction (HSR), although this remains at the clinician's discretion.
There is some debate among clinicians regarding whether HLA-B*57:01 testing is necessary in patients who had previously tolerated abacavir chronically, discontinued its use for reasons other than HSR, and are now planning to resume abacavir. The presence of HLA-B*57:01 has a positive predictive value of ~50% for immunologically confirmed hypersensitivity, indicating that some HLA-B*57:01-positive individuals can be, and have been, safely treated with abacavir. However, the guideline authors were unable to find any data to show that HLA-B*57:01-positive individuals with previous, safe exposure to abacavir had zero risk of HSR upon re-exposure. Although there are isolated case reports of previously asymptomatic patients developing a hypersensitivity-like reaction after restarting abacavir, there were confounding circumstances. Many of the patients had complicating concomitant illnesses that could have masked an HSR during initial abacavir therapy, and none were immunologically confirmed, making the case reports difficult to interpret. Furthermore, most of these case reports precede the availability of HLA-B*57:01 genetic testing, making it impossible to determine from the published data whether there could be a risk of HSR upon re-exposure to abacavir in previously asymptomatic HLA-B*57:01-positive patients.
In addition, there may also exist a small group of patients who have been on chronic abacavir therapy since before the introduction of HLA-B*57:01 genotyping. Given that virtually all abacavir HSR events occur within the first several weeks of therapy, and that ~50% of HLA-B*57:01 carriers can safely take abacavir, the guideline authors were unable to find any evidence to suggest that HLA-B*57:01-positive individuals on current, long-term, uninterrupted abacavir therapy are at risk of developing HSR. Existing clinical guidelines have a blanket recommendation that all HLA-B*57:01-positive individuals should avoid abacavir, regardless of patient history. Although HLA-B*57:01 genotyping has proven utility in significantly reducing the incidence of both clinically diagnosed and immunologically confirmed hypersensitivity in patients being newly considered for abacavir therapy, the connection between HLA-B*57:01 genotype and risk of HSR in patients with previous asymptomatic abacavir use is less clear.
Recommendations for Incidental Findings
Although other variants in HLA-B are associated with autoimmune diseases and drug response phenotypes, they have not been associated with abacavir HSR.
Abacavir skin patch testing may be performed after a case of clinically diagnosed HSR to determine whether it can be immunologically confirmed. At this time, skin patch testing is an investigational procedure, and the results should be interpreted only by an experienced immunologist. More details on skin patch testing can be found in the Supplementary Materials and Methods online (see the "Availability of Companion Documents" field).
Table 2. Recommended Therapeutic Use of Abacavir in Relation to HLA-B Genotype
||Implications for Phenotypic Measures
||Recommendations for Abacavir
||Classification of Recommendations
|Noncarrier of HLA-B*57:01
||Low or reduced risk of abacavir hypersensitivity
||Use abacavir per standard dosing guidelines
|Carrier of HLA-B*57:01
||Significantly increased risk of abacavir hypersensitivity
||Abacavir is not recommended
HLA-B, human leukocyte antigen B
Strength of Therapeutic Recommendations
Strong: The evidence is high quality and the desirable effects clearly outweigh the undesirable effects.
Moderate: There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects.
Optional: The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.