JAC Advance Access originally published online on February 22, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):591-593; doi:10.1093/jac/dkl557
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Leading articles |
HLA-B*5701 screening for susceptibility to abacavir hypersensitivity
Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Level 2, North Block, Wellington Street, Perth, WA 6000, Australia
* Corresponding author. Tel: +61-89-224-2899; Fax: +61-89-224-2920; E-mail: s.mallal{at}murdoch.edu.au
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The introduction of highly active antiretroviral therapy (also known as combination therapy) has transformed the nature of HIV infection from a severe and ultimately fatal disease to that of a manageable chronic condition. HIV drugs are highly efficacious, but their use comes at the cost of a range of drug-related adverse events, including severe drug hypersensitivity reactions (HSRs) that have been most notably associated with abacavir and nevirapine therapy. This article discusses the issues of pharmacogenetic screening, in the light of the strong genetic association of the HLA-B*5701 allele and the susceptibility to developing abacavir HSRs. It also presents the screening's impact on clinical practice and discusses the practical considerations that influence the introduction and cost-effectiveness of such screening.
Keywords: pharmacogenetics , drug hypersensitivity , HIV , antiretroviral therapy
Since the introduction of highly active antiretroviral therapy (HAART, also known as combination therapy), HIV infection has been transformed in treated patients from a severe and ultimately fatal disease to that of a manageable chronic condition. HAART regimens incorporate a variable cocktail of drugs that commonly include two nucleoside analogue reverse transcriptase inhibitors (NRTIs) and either an HIV protease inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI). The action of the NRTI drug class is to inhibit viral replication through the competitive inhibition of the viral RNA-dependent DNA polymerase that allows the creation of a nascent DNA sequence from its own RNA template, whereas NNRTI drugs function by direct binding and inactivation of the polymerase. HIV protease inhibitors prevent the cleavage of the Gag protein and Gag-Pol protein precursors, thus inhibiting HIV replication at a later stage in the cycle.1 These drugs are highly efficacious, but their use comes at the cost of a range of drug-related adverse events, including severe drug hypersensitivity reactions (HSRs) that have been most notably associated with abacavir (NRTI) and nevirapine (NNRTI) therapy.
Abacavir was introduced into clinical practice for the treatment of HIV-1 infection in 1999. The drug can be prescribed as a stand-alone medication (ZiagenTM) and is also available in combination with one or two other NRTI medications (EpzicomTM/KivexaTM—abacavir + lamivudine and TrizivirTM—abacavir + lamivudine + zidovudine) as co-formulated tablets. This drug is recommended as a second-line drug by the WHO (due to the risk of drug hypersensitivity associated with its use), and although commonly prescribed in developed nations, it represents <0.3% of the anti-HIV medications prescribed in developing nations in the past 2 years.2
Drug hypersensitivity represents the major treatment-limiting toxicity for abacavir use, occurring in 
5–8% of recipients within 6 weeks of commencing therapy.3–5 Diagnosis of this multi-system inflammatory syndrome has been primarily based on clinical criteria and is therefore potentially complicated by the use of concurrent drug therapy or the presence of infections. The clinical classification of abacavir hypersensitivity includes at least two symptoms of fever, rash, nausea, vomiting, headache, respiratory and gastrointestinal symptoms, lethargy, myalgia or arthralgia occurring less than 6 weeks after exposure and resolving within 72 h of withdrawal of the drug. More recently, epicutaneous patch testing, involving the application of 1% and 10% concentrations of abacavir to the skin, has proven to be a useful adjunctive method for confirming suspected abacavir hypersensitivity.6
A role for genetic factors in determining susceptibility to abacavir hypersensitivity was initially suggested by clinical reports of a multisystem inflammatory syndrome that affected only a proportion of susceptible abacavir-treated individuals and only in the earliest phases of treatment. Cases of familial predisposition, and significantly decreased frequency in individuals of African origin, were also consistent with this possibility. Subsequent research published from 2002 onwards has revealed a strong predictive association between carriage of HLA-B*5701 and abacavir HSRs in Caucasian and Hispanic ethnic groups,7–9 sufficient to stratify the predicted risk of abacavir hypersensitivity by identifying low-risk (<1%) and high-risk (>70%) individuals according to the presence or absence of the HLA-B*5701 allele.
Prospective HLA-B*5701 genetic screening has now been instituted in clinical practice in Western Australia among abacavir-naive patients and this has had a dramatic effect reducing the risk of developing abacavir hypersensitivity. From January 2002 until July 2005 (n = 260), there were no cases of drug hypersensitivity among 148 HLA-B*5701-negative abacavir recipients. (However, all three HLA-B*5701-positive patients who commenced abacavir in this study developed definite abacavir hypersensitivity.)10 Similar results have been obtained in a more recent study in the UK, where the use of pre-treatment genetic screening among 561 abacavir-naive patients was associated with a significant reduction in the incidence of abacavir HSRs to 0.5%, compared with an incidence of 6.2% among 300 patients in this cohort who commenced abacavir before genetic screening was introduced.11 An unexpected benefit noticed in the Perth cohort since the implementation of testing has been a reduction in the incidence of patients stopping their medication due to any symptoms from a rate of 8% to 4%, despite being negative for HLA-B*5701 and not having an HSR.10
These two independent demonstrations of a significantly reduced incidence of HSR following the introduction of prospective HLA B*5701 screening support the concept that implementation of widespread pre-treatment screening of HIV-1-positive patients is worthy of consideration. To examine this issue further, the benefits of preventing HSR reactions, and the savings made in treatment costs for HSR, need to be compared with the costs of screening. Additionally, the potential impact of patients being incorrectly denied access to treatment which will result in a reduced choice of treatment options (which may or may not be more expensive) for that patient must be considered (summarized in Figure 1).
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In this context, Hughes et al.12 have recently published results from a cost-effectiveness study on the basis of retrospective data from three study cohorts (including two case–control studies). The model utilized in this analysis incorporated estimates of the HLA-B*5701 test's sensitivity and specificity and included the incremental cost of avoiding an HSR as the economic outcome, taking into account the probability of HSR, the probability of testing positive for HLA-B*5701, the costs of treatment of abacavir HSR, the costs of the abacavir-containing regimen and the costs of alternative regimens required if a positive test occurred. They concluded that pre-treatment screening would be a cost-effective use of health-care resources. Thus, for HLA-B*5701 testing, there seems a clear case for pre-treatment screening in Caucasian (and Hispanic) populations where the carriage of the allele is at least 5% and where the genetic association has been clearly demonstrated.13 The relevance of these findings to populations where carriage of the HLA-B*5701 allele is at a significantly lower frequency (such as many Asian and African populations) is less certain. For these populations, the underlying risk of abacavir HSR appears to be reduced when compared with Caucasian populations,4,13,14 thus the savings made per screened individual would decrease and may be outweighed by the costs of screening (Figure 1). These questions are currently being addressed by large-scale prospective international studies such as PREDICT-1 and SHAPE,14 and no generalizations can be made at this stage (for example, early data suggest that HLA-B*5701 is strongly predictive of abacavir HSR in Thai populations).14 One of the innovations that can be complementary to genetic screening for HLA-B*5701 is the incorporation of epicutaneous patch testing to confirm or exclude abacavir hypersensitivity in patients who have experienced some symptoms associated with such reactions. Experience from our cohort and others6 is that reactivity to abacavir patch testing is exclusively restricted to patients with HLA-B*5701 and a lack of reactivity in patients testing as negative for HLA-B*5701 can help the clinician determine whether a true HSR to abacavir has occurred.
There are also practical considerations influencing the widespread implementation of a pharmacogenetic approach to abacavir prescription. Principal among these is the performance of HLA-B*5701 diagnostic methods, which need to utilize molecular typing techniques to resolve HLA alleles within the B17 serological family (e.g. HLA-B*5701, HLA-B*5702, HLA-B*5703 and HLA-B*5801). All high-resolution typing assays designed for this purpose must therefore achieve appropriate specificity and must be rigorously and continually exposed to quality assurance processes to ensure that HLA-B*5701 is accurately diagnosed owing to the potential harm that may caused by prescribing abacavir to a patient who carries the HLA-B*5701 but who has been given a negative test result. In addition, systems must be put into place where the information provided by such screening is available to be evaluated before a drug prescription is filled by hospital pharmacies. For example, in Western Australia, the results of pharmacogenetic testing are now routinely added to the allergy field of the pharmacy system database to ensure that abacavir is not dispensed without prior explicit knowledge and consent of the treating clinician. As stated in a recent review of this topic, screening should promote a ‘more intelligent pharmacovigilance’15 that incorporates a knowledge of the genetic screening result along with ongoing monitoring for evidence of drug hypersensitivity in abacavir-treated patients.
In conclusion, we believe that pharmacogenetic screening for the HLA-B*5701 allele in targeted populations has the potential to significantly improve HIV-1 patient care by allowing for a more informed use of abacavir treatment. The results of the PREDICT-1 and SHAPE trials are eagerly awaited and should further define these cost benefits in different populations and settings. It is also notable that the issues discussed here may be relevant to other severe drug reactions where genetic susceptibility is strongly conferred by the presence of specific HLA-B alleles, such as carbamazepine-associated Stevens–Johnson syndrome (HLA-B*1502)16 and allopurinol HSRs (HLA-B*5801).17
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S. M. and D. N. have received funds for speaking at symposia organized on behalf of GlaxoSmithKline. None to declare for A. L.
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1 Debouck C. (1992) The HIV-1 protease as a therapeutic target for AIDS. AIDS Res Hum Retroviruses 8:153–64.[ISI][Medline]
2 Relative market share of different antiretroviral compounds in low and middle income countries in 2004 and 2005: an analysis of 2 public domain data bases. WHO/UNAIDS Meeting on Forecasting of Antiretrovirals for 2010 (7–8 November 2005). www.who.int/entity/hiv/amds/consumptionAMDS.pdf (12 January 2006, date last accessed).
3 Hetherington S, McGuirk S, Powell G, et al. (2001) Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir. Clin Ther 23:1603–14.[CrossRef][ISI][Medline]
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Cutrell AG, Hernandez JE, Fleming JW, et al. (2004) Updated clinical risk factor analysis of suspected hypersensitivity reactions to abacavir. Ann Pharmacother 38:2171–2.
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Peyriere H, Guillemin V, Lotthe A, et al. (2003) Reasons for early abacavir discontinuation in HIV-infected patients. Ann Pharmacother 37:1392–7.
6 Phillips EJ, Wong GA, Kaul R, et al. (2005) Clinical and immunogenetic correlates of abacavir hypersensitivity. AIDS 19:979–81.[ISI][Medline]
7 Mallal S, Nolan D, Witt C, et al. (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359:727–32.[CrossRef][ISI][Medline]
8 Hetherington S, Hughes AR, Mosteller M, et al. (2002) Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359:1121–2.[CrossRef][ISI][Medline]
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Martin AM, Nolan D, Gaudieri S, et al. (2004) Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc Natl Acad Sci USA 101:4180–5.
10 Rauch A, Nolan D, Martin A, et al. (2006) Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis 43:99–102.[CrossRef][ISI][Medline]
11 Reeves I, Churchill D, Fisher M, et al. (2006) Screening for HLA-B*5701 reduces the frequency of abacavir hypersensitivity reactions. Program and Abstracts of the Eighth International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Francisco, CA, USA pp. S1–S192 Abstract 14.270, Antiviral Therapy 2006; 11: Suppl 3.
12 Hughes DA, Vilar FJ, Ward CC, et al. (2004) Cost-effectiveness analysis of HLA B*5701 genotyping in preventing abacavir hypersensitivity. Pharmacogenetics 14:335–42.[CrossRef][ISI][Medline]
13 Hughes AR, Mosteller M, Bansal AT, et al. (2004) Association of genetic variations in HLA-B region with hypersensitivity to abacavir in some, but not all, populations. Pharmacogenomics 5:203–11.[CrossRef][ISI][Medline]
14 Mosteller M, Hughes A, Warren L, et al. (2006) Pharmacogenetic (PG) investigation of hypersensitivity to abacavir. Program and Abstracts of AIDS 2006 — XVI International AIDS Conference, Toronto, Canada Abstract WEPE0171.http://www.iasociety.org/abstract/show.asp?abstract_id=2194016 (5 February 2007, date last accessed).
15 Phillips EJ. (2006) Genetic screening to prevent abacavir hypersensitivity reaction: are we there yet? Clin Infect Dis 43:103–5.[CrossRef][ISI][Medline]
16 Hung S-I, Chung WH, Jee SH, et al. (2006) Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics 16:297–306.[ISI][Medline]
17 Hung S-I, Chung WH, Liou LB, et al. (2006) HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA 102:4134–9.
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