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Abacavir

The HLA-B*57:01 allele is strongly associated with the development of an abacavir hypersensitivity reaction (HSR). Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) used for treatment of human immunodeficiency virus (HIV). It is generally well tolerated, and common side effects include nausea, headache and diarrhea [Article:18479171]. However, approximately 5-8% of patients experience a HSR within the first 6 weeks of treatment [Article:22378157]. Symptoms of a HSR include at least two of the following: fever, rash, cough, gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain), dyspnea and fatigue [Article:22378157]. These symptoms worsen with continued treatment, but typically improve within 24 hours after discontinuation. However, drug rechallenge after discontinuation of abacavir due to a HSR can result in symptom recurrence within a matter of hours, and potentially life-threatening allergic reactions [Articles:11888582, 10449301]. An overview of abacavir and *57:01 pharmacogenetic studies can be found in Table 1 below; this table is updated as new findings come to our attention.

There is no difference in phenotype depending on whether an individual has one or two HLA-B alleles, so most pharmacogenetic studies only consider whether an individual has the allele or not. Therefore, in this table, "prevalence" of an HLA-B allele refers to how many patients carry that allele, and not the frequency of the allele in the population.

Table 1: Summary of abacavir and HLA-B*57:01 pharmacogenetic studies. p-values and odds ratios (ORs) listed pertain to the risk for an abacavir hypersensitivity reaction (HSR) in patients carrying the *57:01 allele as compared to non-carriers. p-values and ORs were calculated by comparing the frequency of *57:01 in patients who developed an HSR compared to the frequency in abacavir-tolerant controls. Prevalence of *57:01 is listed for patients who developed an HSR (case) and in those who were abacavir-tolerant (control).

Reference	Population	*57:01 prevalence	p-value	Odds ratio (95% CI)
[Article:11943262]	American 1	Case: 37.84 (44%)
		Control: 1/113 (0.9%)
[Article:15016610]	American (White)	Case: 91/189 (48%) 2	8.4 x 10 -23	21.4 (9.5 - 48.1)
		Control: 7/171 (4%)
[Article:15016610]	American (Black)	Case: 3/37 (8%) 2	0.27	3.5 (0.4 - 35.5)
		Control: 1/41 (2%)
[Article:15016610]	American (Hispanic)	Case: 11/51 (22%) 2	2.1 x 10 -4	30.4 (1.7 - 531)
		Control: 0/53 (0%)
[Article:18444831]	American (White)	Case: 42/42 (100%) 3		1945 (110 - 34352)
		Control: 8/202 (4%)
[Article:18444831]	American (Black)	Case: 5/5 (100%) 3		900 (38 - 21045)
		Control: 2/206 (1%)
[Article:11888582]	Australian 4	Case: 14/18 (78%)	< 0.0001	117 (29 - 481)
		Control: 4/167 (2.0%)
[Article:15247625]	British 5	Case: 6/13 (46%)	0.006	7.9 (1.5 - 41.4)
		Control: 5/51 (10%)
[Article:22197535]	Canadian 6	Case: 18/18 (100%)	< 0.0001	6934 (321 - 149035)
		Control: 2/470 (0.4%)
[Article:21091860]	Ugandan	Case: 0/6 (0%) 7
		Control: 0/241 (0%)

^{Table last updated 05/21/2014}

^{1 - 74% White, 13.5% Black, 10.5% Hispanic, 2% unspecified remaining races
2 - Data using a "standard" case definition: cases of hypersensitivity were either "definite/probable" or "possible". Results differed but were still significant for White and Hispanic patients (and still non-significant for Black patients) using a "restrictive" case definition - only cases that were "definite/probable". For "restrictive" case definition data, please refer to the paper directly.
3 - Immunologically confirmed HSRs. For clinically confirmed HSR data, please refer to the paper directly.
4 - 88% Caucasian, 3.5% African, 5.5% Indigenous, 3% Asian
5 - 94% Caucasian, 6% unspecified remaining races
6 - 66% White, 16% Black, 6% Aboriginal, 4.7% Indo-Asian, 3.1% Hispanic, 2% Metis and 2.2% Oriental or Unknown
7 - Clinically confirmed HSRs.}

In 2002, two separate research groups published the first evidence that HLA-B*57:01 was present in a significantly higher percentage of patients showing an abacavir HSR compared to patients with no reaction. These studies were conducted in North American [Article:11943262] and Australian [Article:11888582] populations, and both included 200 participants. This association was subsequently confirmed by another study within a UK population of 64 patients [Article:15247625]. However, these three studies were all conducted using predominantly Caucasian males, limiting their scope. Despite this limitation, several clinics began implementing prospective screening of these alleles with success [Articles:18025891, 17356469, 16758424]. A later study recognized the significance of the allele in White female and Hispanic populations, but found no significant associations for the Black population from this study [Article:15016610]. This was likely due to the lower number of Black patients within the study, and the fact that Black populations tend to have a lower carriage rate of the allele [Articles:15016610, 18444831] - African populations often have *57:01 allele frequencies of less than 2.5%, in contrast to European populations, who often have *57:01 frequencies of 6 - 7% [Article:22378157]. Indeed, a study in Ugandan patients failed to find the *57:01 allele in either their patients with an abacavir HSR or their tolerant controls [Article:21091860].

In 2007, a study known as SHAPE (which included a similar number of White and Black participants) found that Black patients did have fewer cases of abacavir HSRs. However, 100% of both White and Black patients who had immunologically confirmed HSRs were positive for the HLA-B*57:01 allele [Article:18444831]. This suggested that though immunologically confirmed HSRs are rare among Black populations due to the reduced frequency of *57:01, the allele has the same clinical implications in both populations [Article:18444831]. A definitive association between *57:01 and abacavir HSRs came in 2008 with the results of the PREDICT-1 study, a double-blind, prospective, randomized study with 1956 patients from 19 countries. Patients were observed for six weeks and separated into two categories: those that underwent screening for the HLA-B*57:01 allele and were excluded from treatment with abacavir if they tested positive, and those that underwent standard care without any screening. Abacavir HSRs were immunologically confirmed with skin patch testing. The results of the study showed that screening eliminated immunologically confirmed HSRs - 0% of the patients screened had a HSR, while 2.7% of the control population did. This gave the screening a negative predictive value of 100% [Article:18256392]. The positive predictive value of HLA-B*57:01 for abacavir-induced HSRs is typically cited as 55%, implying that around half of all patients who are HLA-B*57:01 positive will not develop an abacavir HSR [Articles:23592889, 21354501, 24565765]. This indicates that other genes and environmental factors are likely involved in the development of an abacavir-induced HSR. Research in this area has been scarce, but several studies have suggested a member of the 70 kilodalton heat shock protein family, HSP70-HOM (also known as HSP1AL), as a potential factor [Articles:15024131, 17545699, 24625462].

This body of evidence led the FDA to implement a boxed warning in 2008, detailing the risk of a HSR for abacavir-treated patients with the HLA-B*57:01 allele. The FDA also recommended that all patients be screened before being treated, and to not use abacavir in HLA-B*57:01-positive individuals. The European Medicines Agency (EMA), and therapeutic guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) [Article:22378157] and the Dutch Pharmacogenetics Working Group (DPWG) [Article:21412232] also recommend genotyping for this allele prior to beginning abacavir treatment.

The HLA-B protein has no direct effect on abacavir pharmacokinetics or pharmacodynamics, and it is still somewhat uncertain exactly how the HLA-B*57:01 allele affects susceptibility to drug hypersensitivity. Several hypotheses exist. One is the hapten concept, which suggests that small compounds such as drugs ("haptens"), bind to the peptides bound to immune receptors such as HLA-B, causing T cells to react and stimulate an immune reaction [Article:17075282]. Another is the p-i concept (pharmacological interactions with immune receptors), which proposes that drugs bind directly and reversibly to immune receptors, stimulating an immune reaction [Article:17075282]. Recent evidence seems to support an alternative hypothesis. Two studies, both published in 2012, found that abacavir can bind non-covalently and with specificity to the F pocket of the peptide-binding groove of HLA-B*57:01 [Articles:22645359, 22722860]. Due to the amino acid residues unique to the *57:01 protein, abacavir can bind only to this particular form of HLA-B. The binding of abacavir to HLA-B*57:01 is believed to change the shape and chemistry of the antigen-binding cleft, and consequently the repertoire of peptides which can bind the molecule. Indeed, both of these papers, as well as an additional paper by Norcross et al., all identified specific changes in the peptides presented by HLA-B*57:01 in the presence of abacavir, as compared to HLA-B*57:01 in the absence of the drug [Articles:22645359, 22722860, 22617051]. Since T cells are trained to be tolerant to a particular repertoire of peptides during their development in the thymus, the alteration in the peptides that can be presented may mean that these new peptides are perceived as foreign. This change would stimulate CD8+ T cell production and response, and would manifest as an abacavir HSR [Articles:22722860, 22645359]. Indeed, CD8+ T cells are abundant in skin biopsies of patients who present with a rash during an abacavir HSR [Article:12409746].

Flucloxacillin

HLA-B*57:01 is also associated with flucloxacillin drug-induced liver injury (DILI). Flucloxacillin is a semi-synthetic penicillin, used widely across Europe and Australia for staphylococcal infection [Articles:19483685, 23032409]. However, it is also associated with the development of cholestatic hepatitis, with risk factors being female sex, age over 55 years old and treatment duration of longer than two weeks [Article:23032409]. A genome-wide association study found that a marker in complete linkage disequilibrium with HLA-B*57:01 was also strongly associated with flucloxacillin DILI. Further analysis found that patients with this allele had a 80-fold increased risk of developing this disease, as compared to those without the allele [Article:19483685]. However, flucloxacillin DILI is a very rare condition, with an estimated prevalence of only 8.5 out of every 100,000 patients. Additionally, the positive predictive value of *57:01 for DILI is only 0.12%, meaning that the majority of patients with *57:01 will not develop flucoloxacillin-induced DILI. Indeed, this positive predictive value indicates that almost 14,000 white patients would need to be tested for *57:01 and excluded from receiving the drug in order to prevent one case of DILI; in non-white or mixed populations, this number could be higher [Article:23291545]. Given the low positive predictive value and the high number needed to test to prevent one case, pre-treatment screening implementation in the clinic is likely not feasible at this time. In their discussion of flucloxacillin HLA-B*57:01 screening, Phillips et al. suggest that a more practical approach is to carefully monitor patients receiving flucloxacillin, and to consider their HLA-B*57:01 genotype only if there is biochemical evidence for hepatitis, at which point the drug can be stopped [Article:23291545]. It is uncertain how the presence of the *57:01 allele leads to an increased risk for flucloxacillin-induced DILI. However, it does not appear to be through the same mechanism as *57:01 and abacavir hypersensitivity: Wuillemin et al. found that in the presence of the HLA-B*57:01 molecule, flucloxacillin stimulated T cells (including CD8+ T cells) according to the p-i concept [Article:23596311]. In a later study, Wuillemin et al. also showed that DILI might be caused by the infiltration of cytotoxic CD8+ and CD3+ T cells into the liver [Article:24731753]. Consideration of the results from both Wuillemin et al. studies provides a possible explanation for the connection between *57:01 and DILI.

Drugs / Other Molecules	Drug (2) abacavir 1 2 3 4 5 6 7 flucloxacillin 8
Diseases	Drug Hypersensitivity 9 10 11 12 13 14 15 drug-induced liver injury 16

Numbered footnotes are links to supporting evidence.