INTRODUCTION — Abacavir is a guanosine nucleoside analog with potent activity against HIV. However, in the premarketing phase of drug development, multiple reports emerged of a hypersensitivity syndrome associated with abacavir, which led to significant morbidity. Rare reports of mortality were associated with failure to recognize this clinical syndrome as drug hypersensitivity.
Research into this syndrome has demonstrated a host predisposition to this drug-associated hypersensitivity reaction, which is based on immunogenetics . Subsequent studies have demonstrated improved drug safety when abacavir use is restricted to patients without this genetic predisposition. This is the first time that an immunogenetic marker has been used in clinical practice to prevent a specific drug toxicity.
This topic will address the epidemiology, immunogenetics, clinical manifestations, clinical management, and screening recommendations for the abacavir hypersensitivity reaction (AHR). Indications for use of abacavir as part of combination antiretroviral therapy (ART) are discussed elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
GENERAL BACKGROUND — The term "human leukocyte antigen (HLA) system" is synonymous with the human major histocompatibility complex (MHC). These terms describe a group of genes on chromosome 6 that encode a variety of cell surface markers, antigen-presenting molecules, and other proteins involved in immune function. The HLA region is divided into three classes and there are three different class I antigens (HLA-A, -B, -C). (See "Human leukocyte antigens (HLA): A roadmap".)
The principal task of the immune system is to recognize and respond to potential pathogens without reacting to the normal components of the individual. Class I HLA molecules present peptide fragments of foreign antigens to CD8+ T cells, which generally have cytotoxic/suppressor function. (See "Major histocompatibility complex (MHC) structure and function".)
IMMUNOGENETIC BASIS FOR AHR — Human leukocyte antigen (HLA) associations with certain rheumatic diseases have been known for several decades . However, interest in HLA background as a potential risk factor for certain drug reactions has only become well defined more recently. Several associations have been drawn between severe hypersensitivity reactions to particular drugs, in particular severe cutaneous adverse drug reactions (SCAR) and specific class I major histocompatibility complex (MHC) backgrounds. These include allopurinol (HLA-B*58:01), carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN; HLA-B*15:02), carbamazepine SCAR (HLA-A*31:01), abacavir hypersensitivity reaction (AHR; HLA-B*57:01) and flucloxacillin drug-induced liver injury (HLA-B*57:01), dapsone SCAR (HLA-B*13:01), and vancomycin drug-induced eosinophilia and systemic symptoms (HLA-A*32:01), amongst others [2-10]. (See "Drug hypersensitivity: Classification and clinical features".)
A strong body of evidence from both basic science and clinical research has demonstrated that abacavir hypersensitivity is exclusively restricted by the HLA allele HLA-B*57:01 and is mediated by the activation of CD8+ T-lymphocytes that then release inflammatory cytokines and result in the clinical syndrome of AHR [11-15]. The rapid and direct noncovalent binding of abacavir to HLA-B*57:01 without the requirement for metabolism of the drug also explains the clinical symptoms of hypersensitivity, including dose-related escalation of symptoms and rapid offset of symptoms following drug cessation. (See 'Clinical syndrome' below.)
The precise mechanism for how abacavir interacts with HLA and host peptides has been revealed by biochemical and structural studies from independent groups. These studies demonstrated that abacavir binds noncovalently to the floor of the peptide-binding groove of HLA-B*57:01 with exquisite specificity to alter the self-peptides that are presented to the immune system (figure 1) [16-19]. This specificity explains the 100 percent negative predictive value of HLA-B*57:01 testing for hypersensitivity, which underpins its utility as a screening test. (See 'Sensitivity and specificity of HLA-B*57:01 screening' below.)
An HLA-B*57:01-transgenic mouse model has provided a possible mechanism to explain why some HLA-B*57:01-positive individuals tolerate abacavir. Although it is likely that in all HLA-B*57:01-positive abacavir-exposed patients, abacavir binds noncovalently to the floor of the peptide-binding groove of HLA-B*57:01 and alters the repertoire of endogenous peptides presented to CD8+ T cells (figure 1); 45 percent of HLA-B*57:01-positive individuals exposed to the drug do not develop AHR . CD4+ T cells may have a role in establishing tolerance to the altered peptide repertoire in such individuals who do not develop hypersensitivity [21,22].
Ex vivo data strongly support a role for cytotoxic T cells in the pathogenesis of AHR:
●The production of interferon-gamma was specifically induced by abacavir exposure in peripheral blood mononuclear cells (PBMCs) obtained from hypersensitive patients carrying the HLA-B*57:01 allele compared with tolerant controls .
●Patients with a history of AHR had increased levels of tumor necrosis factor (TNF-alpha) in response to ex vivo abacavir stimulation; these responses were abrogated by CD8+ T cell depletion [11,12,14].
●Significant CD8 T cell proliferation in response to abacavir stimulation occurred in patients with a positive abacavir skin patch test compared with stimulation with control antigens . Furthermore, skin biopsies from both the skin rash of AHR and a positive patch test following AHR have demonstrated abundant CD8+ T cells. (See 'Skin patch testing' below.)
In addition to its role in AHR, HLA-B*57:01 has been shown to play an important role in HIV control, viral set point, and has been overrepresented in populations of long-term nonprogressors and elite controllers. HLA-B*57:01 is associated with early, broad, and strong HIV-specific T cell responses, particularly to epitopes in the gag protein. The virus cannot mutate to escape these responses without incurring a large loss of replicative capacity . (See "The natural history and clinical features of HIV infection in adults and adolescents".)
EPIDEMIOLOGY OF AHR — The epidemiology of AHR varies according to whether it is defined by clinical symptoms alone or with supportive diagnostic testing, such as skin patch testing. Since the manifestations are nonspecific, AHR can be confused with other clinical syndromes, leading to substantial overdiagnosis. (See 'Differential diagnosis' below.)
Clinical diagnosis of AHR — In early postmarketing experience, AHR was described in 4 to 8 percent of patients .
●A large retrospective review of 200,000 patients exposed to abacavir (from 1996 to 2000) was undertaken to determine the incidence of abacavir-related hypersensitivity events . Cases were classified as definitive or probable; definitive cases included patients whose symptoms returned on re-exposure to the drug. Based on the 1302 cases identified in clinical trials, the calculated incidence of hypersensitivity was 4 percent.
●A prospective clinical trial, which evaluated whether abacavir could be given once daily rather than twice daily, found that the incidence of AHR was similar regardless of dosing frequency (9 versus 7 percent) .
Association of AHR and race — In the early use of abacavir, AHR became the main reason for drug discontinuation in approximately 8 percent of treated patients. No obvious risk factors emerged for this syndrome, although the incidence of this reaction appeared to vary according to race:
●In a study of 725 patients who underwent HLA-B*57:01 screening (one-third of whom were Black), 5.7 percent of the participants overall were HLA-B*57:01-positive, including 7.2 percent of White and 2.8 percent of Black Americans .
●A multivariate analysis of 5332 abacavir-exposed patients found that the risk was generally lower in Black populations than among other ethnic groups (3 percent hypersensitivity; OR 0.59; 95% CI 0.38-0.91) .
EVIDENCE OF LINK BETWEEN HLA BACKGROUND AND AHR
Carriage rates of HLA-B*57:01 and risk of AHR — In 2002, two independent groups found a strong association between AHR and carriage of the major histocompatibility complex class I allele HLA-B*57:01 marker [28,29].
●In a prospective study of Australian patients exposed to abacavir, HLA-B*57:01 was present in 14 (78 percent) of the 18 patients with abacavir hypersensitivity and in 4 (2 percent) of the 167 abacavir-tolerant patients .
●In a retrospective, case-control study of mainly White men with HIV, HLA-B*57:01 was present in 39 (46 percent) of 84 patients clinically diagnosed with AHR versus 4 (4 percent) of 113 controls .
Studies in mainly White populations suggested HLA-B*57:01 carriage rates of approximately 4 to 8 percent (figure 2) [30-32]. The carriage rate of HLA-B*57:01 in Black Americans is thought to be 2 to 3 percent; however, rates of <1 percent have been cited in certain African and Asian populations . Frequencies in smaller and rarer populations can be found at www.allelefrequencies.net as this information becomes available.
Testing performance among different racial populations — Although it was initially perceived that human leukocyte antigen (HLA) testing lacked predictive value across all racial groups , a retrospective case-control study using patch test confirmation has shown that HLA-B*57:01 was a sensitive test for AHR regardless of race . Patients were identified through chart review and were classified as having AHR either through clinical suspicion alone (defined as having at least two symptoms or signs consistent with AHR) or based on clinical findings supplemented with a positive skin patch test. Control subjects were racially matched patients who had tolerated abacavir for at least 12 weeks. A skin patch test was used to define patients with true immunologically mediated AHR. The study demonstrated the following results:
●Forty-two (32 percent) of 130 White patients and 5 (7 percent) of 69 Black patients who had clinically suspected AHR also had a positive skin patch test.
●All White patients with immunologically confirmed disease were HLA-B*57:01-positive (100 percent sensitivity); among White patients with clinically suspected AHR, the sensitivity was only 44 percent (57 of 130 patients tested positive for HLA-B*57:01). Specificity among White control patients was 96 percent.
●Among Black patients with immunologically confirmed disease, five of five were HLA-B*57:01-positive (100 percent sensitivity); among patients with clinically suspected AHR, the sensitivity was only 14 percent (10 of 69 tested positive for HLA-B*57:01). Specificity among Black control patients was 99 percent.
The authors concluded that although immunologically confirmed cases of AHR are less common in Black persons, HLA-B*57:01 still performed extremely well as an immunogenetic marker of risk. This study also demonstrated that false-positive clinical diagnoses overshadow true immunologically mediated hypersensitivity reactions, particularly in low prevalence races. The sensitivity and specificity of HLA-B*57:01 testing is discussed below. (See 'Diagnosis' below.)
AHR typically presents with a combination of symptoms, including fever (which is almost always present), constitutional symptoms (eg, malaise, dizziness, and headache), and gastrointestinal disturbances (eg, nausea, vomiting, diarrhea) [24,35-46]. In one retrospective study, respiratory symptoms (eg, dyspnea, cough) occurred in approximately one-third of patients . The median time to onset of symptoms in patch test-confirmed cases is seven to eight days, although symptoms have been reported within one to two days of abacavir initiation [35-37]. In a large trial of patients initiating abacavir, hypersensitivity reactions that were patch-test confirmed presented within three weeks of starting abacavir .
Rash is often a late symptom that is absent in up to 30 percent of patients with AHR. In addition, up to 3 percent of patients will develop isolated rash without other symptoms, and this does not constitute AHR.
Signs may also include tachycardia and hypotension, particularly on rechallenge. One case series also reported large painful cervical and axillary lymph nodes in association with AHR . (See 'Skin patch testing' below.)
DIAGNOSIS — The current diagnostic approach to AHR is based on clinical diagnosis and the presentation of multiple symptoms and signs compatible with AHR. There is no diagnostic test that has been shown to have 100 percent sensitivity, and there are no consistent laboratory findings that develop at the time of AHR. The differential diagnosis of AHR is discussed below. (See 'Differential diagnosis' below.)
Although HLA-B*57:01 is useful as a genetic screening test before abacavir is prescribed, it should not be used as a diagnostic test for AHR after the drug has been started. It remains theoretically possible that a second rare human leukocyte antigen (HLA) allele may also mediate AHR; thus, a negative HLA-B*57:01 result should not be used to eliminate the diagnosis of AHR in previously exposed patients who developed a compatible clinical syndrome. Such an approach has not been studied and carries the potential risk of morbidity and mortality with rechallenge in a patient with a rare predisposing HLA allele.
Similarly, abacavir patch testing has less than 100 percent diagnostic sensitivity and a negative patch test should not be used as the basis for abacavir rechallenge.
AVAILABLE TESTING METHODS FOR AHR — Ideally, all patients should be screened for HLA-B*57:01 prior to abacavir therapy. Screening for HLA-B*57:01 represents a major advance in the care of patients with HIV and remains the mainstay in preventing AHR and its associated morbidity and mortality . However, if testing is not available, abacavir can be initiated in conjunction with a clinical management program in select settings. (See 'Recommendations' below.)
Rechallenge with abacavir in patients who have a documented clinical syndrome compatible with AHR is not recommended. In contrast, patients who have been "labeled" with a diagnosis of AHR, but whose clinical syndrome was clearly not compatible with AHR (eg, single symptom disease, such as isolated skin rash), can have abacavir reintroduced if their HLA-B*57:01 screening test is negative. (See 'Clinical management' below.)
Sensitivity and specificity of HLA-B*57:01 screening — Initial doubt was cast on the generalizability of HLA-B*57:01 testing since further studies showed particularly low sensitivities of HLA-B*57:01 for clinically diagnosed abacavir hypersensitivity in Black patients [29,34]. However, it became apparent that false-positive clinical diagnoses were responsible for this discrepancy . This was further supported by the consistent 2 to 7 percent rates of clinically diagnosed abacavir hypersensitivity reaction in the nonabacavir arm of randomized double-blinded placebo-controlled studies .
A retrospective, case-control study (SHAPE) in a racially diverse population showed 100 percent sensitivity of HLA-B*57:01 for skin patch-confirmed AHR, suggesting a 100 percent negative predictive value of HLA-B*57:01 testing for abacavir hypersensitivity in patients of both White and Black populations . This study supported broad applicability of genetic screening. The implications of screening in a model incorporating White and Black populations are shown in the figure (algorithm 1). Details of this study are discussed above. (See 'Evidence of Link between HLA background and AHR' above.)
The 100 percent negative predictive value of HLA-B*57:01 screening was confirmed in clinical trials of prospective screening prior to abacavir exposure. (See 'Screening prior to abacavir exposure' below.)
Skin patch testing — In patients with a history of possible AHR, skin patch testing can help define those with true immunogenetically mediated disease versus a false-positive clinical diagnosis [15,37,40]. The patch test has been demonstrated to be reliable even in patients with a remote history of abacavir hypersensitivity .
Although a positive patch test supports the diagnosis of AHR, a negative abacavir patch test result should not be used to justify rechallenge with abacavir as the sensitivity is less than 100 percent . In the PREDICT-1 trial, the diagnostic sensitivity of abacavir skin patch testing was calculated to be 87 percent [36,40].
Skin patch testing should only be performed in patients with a history of possible AHR since a positive patch test will only develop in genetically susceptible patients who are "immunologically primed" by prior ingestion of abacavir. Thus, skin patch testing is not helpful for predicting risk of AHR in unexposed patients. However, it has helped to reinforce the strong association between HLA-B*57:01 and AHR. As an example, of 95 patients with clinically suspected abacavir hypersensitivity and positive patch tests described in three studies, 100 percent carried HLA-B*57:01 .
The patch testing procedure entails applying abacavir in concentrations of 1% and 10% in petrolatum and controls with readings at 24 and 48 hours after patch application. Patch test reagents are not commercially available, but as with other drugs, can be compounded from commercially available abacavir tablets by pharmacists or in certain clinical settings . A positive patch test result, measured by a visible and palpable cutaneous response, implies a delayed hypersensitivity response to abacavir (picture 1 and figure 3). More detailed information on patch testing is presented in a separate topic review. (See "Patch testing".)
DIFFERENTIAL DIAGNOSIS — The symptoms of AHR are nonspecific and can be difficult to distinguish from other etiologies. This problem of false-positive clinical diagnosis was highlighted in randomized, double-blinded, controlled clinical trials, where AHR was reported in 2 to 7 percent of patients who were not receiving abacavir [41,42].
The differential diagnosis of abacavir hypersensitivity syndrome includes:
●Infectious processes (eg, influenza) 
●Immune reconstitution inflammatory syndrome (IRIS) (see "Immune reconstitution inflammatory syndrome")
●Other drug-related adverse events (eg, rash or diarrhea) (see "Drug hypersensitivity: Classification and clinical features")
In one study of 15 patients with abacavir hypersensitivity and 30 patients with influenza, rash and gastrointestinal symptoms were noted in approximately half of the patients with AHR versus 6 percent of those with influenza .
Drug-associated rash is an important cause of drug discontinuation in patients with HIV and is associated with other antiretroviral agents besides abacavir (eg, nevirapine, efavirenz, etravirine, atazanavir) or antibacterials (eg, trimethoprim-sulfamethoxazole) [13,49]. (See "Overview of antiretroviral agents used to treat HIV", section on 'Non-nucleoside reverse transcriptase inhibitors (NNRTIs)'.)
Diarrhea and other gastrointestinal symptoms are commonly associated with many agents in the protease inhibitor class; in AHR gastrointestinal symptoms are usually associated with other constitutional symptoms as well. (See "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)
Abacavir does not cause Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and AHR should not be confused with drug reaction with eosinophilia and systemic symptoms as typically there is limited organ involvement and no classical eosinophilia or hematologic abnormalities with AHR. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
CLINICAL MANAGEMENT — Abacavir should be immediately discontinued in any patient who develops clinical signs and symptoms consistent with AHR, whether or not the patient has had genetic screening . Symptoms usually remit promptly after drug discontinuation. Treatment during this time is mainly supportive. Ongoing symptoms may indicate an alternative diagnosis. (See 'Differential diagnosis' above.)
Once the patient has improved, rechallenge with abacavir, or any formulation containing abacavir (eg, the single-pill regimen dolutegravir-abacavir-lamivudine), in a patient with suspected AHR is absolutely contraindicated. Rechallenge to abacavir after an initial hypersensitivity reaction can result in a more rapid, severe, and potentially life-threatening reaction [44-46,50]. In the retrospective study discussed above, rechallenge resulted in reappearance of symptoms within hours; hypotension was present in 25 percent of these recurrent reactions . Among patients who received abacavir in clinical trials, the mortality rate was 0.03 percent (3 per 10,000 patients).
For a diagnostic evaluation to investigate the patient with possible AHR, (see 'Diagnosis' above).
EARLY STUDIES OF IMMUNOGENETIC SCREENING — As noted above, epidemiologic data demonstrated a strong association between the presence of the HLA-B*57:01 allele and a history of AHR. Subsequent observational studies performed in Australia, the United Kingdom, France, and North America have demonstrated that immunogenetic screening can significantly reduce the risk of an adverse drug-related hypersensitivity reaction [26,30-33,51,52].
●In a single cohort study of mainly White patients starting abacavir from 2002 to 2005, the incidence of AHR was 2 percent in 151 patients; this rate was much lower than historical controls where 8 percent experienced AHR prior to the introduction of genetic screening . No cases of AHR were described in the 138 HLA-B*57:01-negative patients. Genetic screening was also associated with reduction in the clinical overdiagnosis of hypersensitivity reactions.
Large prospective trials have helped to further define the role of immunogenetic screening to prevent AHR.
CLINICAL TRIALS OF HLA-B*57:01 SCREENING — Several trials have demonstrated the improved safety of drug administration with prior immunogenetic screening.
PREDICT-1 trial — The Prospective Randomized Evaluation of DNA Screening in a Clinical Trial (PREDICT-1) was a double-blinded study enrolling 1956 predominantly White patients across 265 European and Australian sites . This was the first study of its kind to examine the clinical effectiveness of a genetic screening test to prevent toxicity from a specific drug. Patients were randomly assigned to either prospective or retrospective HLA-B*57:01 testing before initial abacavir exposure and were followed for six weeks. All patients with a clinical diagnosis of AHR underwent skin patch testing six to ten weeks following an AHR diagnosis for immunologic confirmation. The primary objective was to test the hypothesis that prospective screening for HLA-B*57:01 and the exclusion of patients carrying the allele from abacavir treatment reduces the incidence of hypersensitivity. The study demonstrated the following results:
●Of the 980 patients in the prospective screening group, 55 (6 percent) were excluded from the main study because they were HLA-B*57:01 positive.
●The incidence of clinically diagnosed hypersensitivity reactions was significantly lower in the prospective screening group compared with the control group (3.4 versus 7.8 percent). For clinically diagnosed cases, the presence of HLA-B*57:01 had a positive predictive value of 61 percent and a negative predictive value of 96 percent.
●No immunologically confirmed cases (ie, patch test positive) of AHR were diagnosed in the prospective screening group, whereas 23 immunologically confirmed cases occurred in the control group (2.7 percent). Thus, for immunologically confirmed hypersensitivity reactions, the HLA-B*57:01 allele was associated with a positive predictive value of 48 percent and a negative predictive value of 100 percent. After adjustment for the 87 percent diagnostic sensitivity of patch testing, HLA-B*57:01 had a 55 percent positive predictive value for true immunologically mediated AHR, and this is the value that is most relevant to clinical practice.
●One hundred patients who were abacavir tolerant had negative skin patch testing for a specificity of 100 percent. By chance, none of these patients were HLA-B*57:01 positive.
●In a multivariate model, concurrent use of a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor could account for approximately 45 percent of the clinically diagnosed cases of AHR that did not have immunologic confirmation, suggesting that symptom overlap was responsible for a false-positive clinical diagnosis of AHR in some patients.
This study supports that HLA-B*57:01 is an ideal screening test to prevent immunologically confirmed AHRs. Immunologically confirmed AHRs were eliminated in the screened arm, giving a 100 percent negative predictive value for HLA-B*57:01 screening. In contrast, the overall positive predictive value of HLA-B*57:01 testing for AHR was 55 percent, which suggests that HLA-B*57:01 is necessary, but not sufficient, for the development of AHR.
ARIES trial — The Atazanavir Ritonavir Induction/Simplification with Epzicom Study (ARIES) was the first treatment trial to prospectively employ HLA-B*57:01 screening in its design . In this study of 725 patients, 5.7 percent were HLA-B*57:01-positive. Out of 517 HLA-B*57:01-negative individuals enrolled, only four (0.8 percent) were diagnosed with AHR during the study, and all four had a negative abacavir skin patch test performed at least six weeks following the original reaction .
SCREENING PRIOR TO ABACAVIR EXPOSURE
Whom to screen — For patients who are being considered for therapy with abacavir, we recommend HLA-B*57:01 screening to decrease the risk of abacavir hypersensitivity reaction. (See 'Recommendations' below and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Considerations prior to initiating treatment'.)
Although the carriage rate of HLA-B*57:01 is low in many non-White populations , and it has been argued that screening may not be cost effective in such populations in which the epidemiology of HLA-B*57:01 carriage has been defined , evidence suggests that:
●The 100 percent negative predictive value of screening generalizes across ethnicity .
●Screening also decreases the 2 to 7 percent false-positive clinical diagnosis regardless of ethnicity [26,30-32,51,54].
●Technologies for screening are feasible and cost effective [55-57].
Furthermore, selective screening on the basis of the perceived race or ethnic background of the patient in areas where screening is already available is unlikely to be practical, ethical, or safe because of increasing rates of racial or ethnic admixture and because of the unreliability of the assignment of race or ethnic group by the patient or his or her clinician . The Federal Drug Administration (FDA) has recommended that all patients be informed about the availability of pharmacogenetic testing prior to abacavir administration .
Role of skin patch testing — Skin patch testing is only useful in patients who have had an AHR. As an example, patch testing was negative in 13 HLA-B*57:01-positive individuals (7 with HIV, 6 without HIV) without prior abacavir exposure, despite the presence of circulating abacavir-reactive T cells . Thus, patch testing cannot be used as a screening tool since the results of the test depend upon prior abacavir ingestion and immunologic priming. (See 'Diagnosis' above.)
Recommendations — If abacavir is being considered as part of an antiretroviral treatment regimen, we recommend the use of HLA-B*57:01 screening in abacavir-naïve subjects to prevent abacavir hypersensitivity. Testing should be performed regardless of race. (See 'Association of AHR and race' above.)
●An abacavir-containing regimen can be used in patients who have tested negative for HLA-B*57:01 [61,62]. The choice of regimen is discussed separately. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Commonly used agents'.)
●Those who are found to have a positive HLA-B*57:01 screening test should not be prescribed abacavir and should have this information recorded prominently in their medical records to avoid future exposure.
HLA-B*57:01 testing is now widely available through numerous laboratory providers in areas of the developed world where the frequency of HLA-B*57:01 is high, and initiation of abacavir without HLA-B*57:01 screening is not recommended. However, in areas where HLA-B*57:01 testing is not available and the prevalence of HLA-B*57:01 is very low (<1 percent), such as Africa and Southeast Asia, abacavir may be initiated with appropriate clinical counseling and monitoring for any signs of hypersensitivity reaction .
In the United States, where guidelines have recommended screening for HLA-B*57:01 prior to abacavir prescription since 2008, screening has effectively eliminated abacavir hypersensitivity as a clinical entity. Data from the OPERA prospective clinical cohort suggest that HLA-B*57:01 screening prior to abacavir prescription in the United States increased from 43 percent in 2009 to 84 percent in 2015, with a resultant decline in the reported number of probable abacavir hypersensitivity reaction cases from 1.3 percent prior to screening to 0.2 percent in 2015 . However, 16 percent of individuals were not screened prior to abacavir prescription, which highlights the need to reinforce screening as the standard of care.
MONITORING OF PATIENTS ON ABACAVIR — Patients should be counseled on the potential signs and symptoms of an AHR . Genetic screening for HLA-B*57:01 improves the safety of prescribing abacavir by ensuring that genetically predisposed individuals are not exposed and sensitized to abacavir. However, clinical vigilance for hypersensitivity to abacavir remains the cornerstone of management, regardless of the results of HLA-B*57:01 testing. (See 'Clinical syndrome' above and "Overview of antiretroviral agents used to treat HIV".)
Abacavir should be stopped if patients develop symptoms consistent with AHR, despite negative HLA-B*57:01 testing. In these cases, the HLA-B*57:01 typing should be repeated. Rechallenge with abacavir should not be performed without appropriate clinical evaluation. Such patients should be managed in conjunction with an immunologist; work up may include patch testing and possibly ex vivo/in vitro testing.
Although there have been case reports of possible AHR reported in patients who have screened negative for HLA-B*57:01, none of the cases have met clinical and immunological criteria for AHR [32,65]. Reasons for having AHR in the setting of a negative HLA-B*57:01 are as follows:
●Some HLA-B*57:01-positive patients may have been mistakenly been identified as being HLA-B*57:01 negative (ie, laboratory error).
●For other patients, a second rare human leukocyte antigen (HLA) association may yet be found to exist. The appropriate and safe way to find such a second HLA allele is through careful clinical and immunological investigation of HLA-B*57:01-negative patients who develop clinical symptoms compatible with AHR. Patients should be referred to an immunologist to help with this investigation.
LABORATORY TESTING AND QUALITY ASSURANCE — With the implementation of systematized screening efforts, maintenance of robust quality assurance programs will be necessary to maintain a high and consistent standard of laboratory testing.
One study distributed DNA panels to seven laboratories for blinded typing of the HLA-B*57:01 allele and found excellent concordance and performance (100 percent specificity and 99.4 percent specificity) . Currently, the Royal College of Pathologists of Australasia is internationally administering a program to ensure consistency of laboratory testing (enroll at: www.rcpaqap.com.au/).
Technologies available for HLA-B*57:01 screening include not only full high-resolution human leukocyte antigen (HLA) typing (DNA sequence-based typing), but also PCR-based techniques [55,57], and flow cytometry  with a monoclonal antibody to HLA-B57/58 (B17). Patients can receive abacavir based on a negative B17 monoclonal antibody test; however, a positive test must be confirmed to be specifically HLA-B*57:01 through high resolution HLA typing or a PCR-based HLA-B*57:01-specific assay. Flow cytometric techniques are particularly attractive for their potential ease for incorporation in baseline HIV laboratory testing, which already includes CD4+ and CD8+ T cell testing. High-resolution HLA typing has a longer turnaround time, is costly, and is largely restricted to specialty immunogenetic/transplant laboratories.
One group advocated the use of HCP5, a HLA-B*57:01 haplospecific marker only 100 kb centromeric from HLA-B, as a surrogate screening test for HLA-B*57:01. However, clinical and patch test-confirmed AHR has occurred in the setting of HCP5 negativity in an HLA-B*57:01-positive individual, suggesting that HLA-B*57:01 is necessary for the development of AHR and should remain the gold standard as a genetic screening test for AHR; HCP5 testing cannot be safely applied as a screening test [20,67].
COST-EFFECTIVENESS — From clinical trial and observational data in a White population, approximately 13 patients would need to be screened to prevent one case of clinically false-positive or true immunologically mediated abacavir hypersensitivity, suggesting that screening is cost-effective . One analysis suggested that routine testing for HLA-B*57:01 appeared to be a cost-effective measure and that overall cost is driven by the treatment regimen .
Baseline screening for HLA-B*57:01 is likely to be cost-effective in routine HIV practice due to :
●The availability of rapid and inexpensive tests for HLA-B*57:01 screening
●The impact of testing on improving the clinical diagnosis of AHR
●The morbidity associated with AHR, including hospitalization and death, when screening is not employed
●The negative impact on HIV care when a false clinical diagnosis of abacavir hypersensitivity is made and treatment is discontinued
FUTURE RESEARCH — As noted above, HLA-B*57:01 is necessary, but not sufficient, for the development of abacavir hypersensitivity. Since the positive predictive value of HLA-B*57:01 for abacavir hypersensitivity is 55 percent, research is ongoing to identify why 45 percent of patients with HLA-B*57:01 can tolerate the drug . One study suggested that genes outside the major histocompatibility complex, such as endoplastic reticulum aminopeptidase 1, may be important in explaining part of this positive predictive value gap . The altered peptide repertoire model that explains the basis of abacavir hypersensitivity may apply to other drug hypersensitivity syndromes [16-19]. In keeping with the altered peptide repertoire model, recent work looked at single-cell RNA sequences at the site of a positive patch in a patient 14 years after AHR, suggesting that polyclonal T effector memory T cells are recruited to the site of abacavir exposure; these T cells express a profile consistent with a memory T cell response to viral pathogens . Further work will define HLA-peptide drug interactions and provides a potential approach for preclinical screening of drugs for immunological toxicities.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in nonpregnant adults and adolescents".)
SUMMARY AND RECOMMENDATIONS
●Abacavir is a nucleoside analog with potent activity against HIV; however, a proportion of patients develop a hypersensitivity reaction to this drug after exposure, which can lead to significant morbidity. (See 'Introduction' above.)
●A strong body of evidence from both basic science and clinical research has demonstrated that abacavir hypersensitivity is associated with HLA-B*57:01 background and is mediated via CD8+ T-lymphocytes. No human leukocyte antigen (HLA) allele other than HLA-B*57:01 has been associated with immunologically confirmed abacavir hypersensitivity to date; the mechanistic basis for this exclusivity is based on the specificity of abacavir binding to the HLA-B*57:01 molecule. (See 'Immunogenetic basis for AHR' above.)
●In the prescreening era, abacavir hypersensitivity reaction (AHR) was diagnosed in 4 to 8 percent of treated patients. Postscreening AHR has been markedly reduced, with an incidence of 0.2 percent or lower. (See 'Epidemiology of AHR' above.)
●AHR typically presents with a combination of symptoms, including fever, rash, gastrointestinal disturbances, and other constitutional symptoms. (See 'Clinical syndrome' above.)
●Abacavir should be discontinued in a patient with signs and symptoms of AHR that progress without another explanation. Once the patient has improved, rechallenge with abacavir, or any formulation containing abacavir (eg, the single-pill regimen dolutegravir-abacavir-lamivudine), in a patient with suspected AHR is absolutely contraindicated. (See 'Clinical management' above.)
●Skin patch testing helps to define those patients with a history of possible AHR with true immunogenetically mediated disease versus a false-positive clinical diagnosis. As with other drugs, skin patch testing is useful as an adjunctive testing tool but should not be used as the basis for abacavir rechallenge in those who have a clinical history consistent with AHR. (See 'Diagnosis' above.)
●For patients who are being considered for therapy with abacavir, we recommend HLA-B*57:01 screening to decrease the risk of AHR (Grade 1A). This is consistent with recommendations from guideline committees. (See 'Screening prior to abacavir exposure' above.)
●Although genetic screening for HLA-B*57:01 improves the safety of prescribing abacavir, appropriate counseling of patients of potential signs and symptoms is still indicated, even if their screening test is negative. (See 'Monitoring of patients on abacavir' above.)
ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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