Journal of Antimicrobial Chemotherapy (2007) 59, 591– 593
doi:10.1093/jac/dkl557
Advance Access publication 22 February 2007
HLA-B*5701 screening for susceptibility to abacavir hypersensitivity
Andrew Lucas, David Nolan and Simon Mallal*
Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University,
Level 2, North Block, Wellington Street, Perth, WA 6000, Australia
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 nonnucleoside 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 þ lamivudine and TrizivirTM —
abacavir þ lamivudine þ 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
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*Corresponding author. Tel: þ 61-89-224-2899; Fax: þ61-89-224-2920; E-mail:
[email protected]
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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 drugrelated 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.
Leading article
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
Common allele
Rare allele
(13 patients screened to
detect 1 HLA-B*5701
patient in Perth)
(91 patients screened
to detect 1 HLA-B*1502
patient in Perth)
Positive predictive
value, low
Positive predictive
value, high
(0.94 for ABC in Perth)
High average cost of
HSR treatment
Higher cost of
alternate therapy
Low average cost of
HSR treatment
Lower cost of
alternate therapy
Favours testing
Disfavours testing
Figure 1. Where does the balance fall for pharmacogenetic screening?
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abacavir-naive patients and this has had a dramatic effect reducing the risk of developing abacavir hypersensitivity. From
January 2002 until July 2005 (n ¼ 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).
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
Leading article
Transparency declarations
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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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