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HIV and AIDS
Personal Experiences of HLA-B*5701 Genetic Screening in
Routine Clinical Practice
a report by
Jürgen K Rockstroh,
1
Phillip E Hay
2
and David A Leather
3
1. Department of Medicine I, University of Bonn; 2. St George’s Hospital Medical School, University of London; 3. GlaxoSmithKline, UK
Abacavir (Ziagen
®
), also found in the co-formulations Kivexa™ – abacavir median time to onset being 11 days – and in at least 90% of cases
+ lamivudine (3TC) – and Trizivir™ – abacavir + lamivudine + zidovudine symptoms appear within the first six weeks of starting abacavir.
11
The
(ZDV) – is a nucleoside reverse transcriptase inhibitor (NRTI) that is widely reaction is a multi-organ event and 80% of patients present with at least
used in the treatment of HIV-1 infection.
1
It is generally well tolerated and three symptoms, which commonly include fever (80%), rash (70%),
is recommended by the World Health Organization (WHO)
2
and the gastrointestinal symptoms (50%) and lethargy/malaise (40%).
11
Symptoms
European AIDS Clinical Society (EACS) Guidelines
3
as an option for first- worsen with continued therapy but generally resolve within 72 hours of
line combination therapy. However, a small number of patients develop cessation of abacavir.
11
It is imperative that abacavir therapy is immediately
hypersensitivity reactions (HSRs) to the drug, the outcomes of which can and permanently discontinued if an HSR is diagnosed or cannot be excluded,
be potentially life-threatening, particularly in the context of re-exposure as the severity and rapidity of the reaction increases on re-challenge and can
to abacavir following initial development of hypersensitivity. be potentially fatal.
15
The non-specific symptoms, together with the variable
presentation and frequent co-administration of other antiretroviral drugs
with potentially similar adverse event profiles, present the physician with
The major histocompatibility
difficulties when diagnosing abacavir HSR. Indeed, several blinded
comparative studies have misdiagnosed abacavir HSR in 2–7% of patients
complex class I allele HLA-B*5701 …
not receiving abacavir.
16–18
is now the most extensively
studied pharmacogenetic marker
A Genetic Basis for Abacavir Hypersensitivity
A genetic basis for abacavir hypersensitivity was proposed following a
in HIV therapeutics. number of observations, including reports of a multisystem inflammatory
syndrome that developed in the early phases of treatment in a small
percentage of abacavir-treated patients,
6,14
familial disposition data
19
and
The signs and symptoms of abacavir HSR are non-specific and can the fact that abacavir HSRs were more common among Caucasians than
be difficult to distinguish from conditions such as influenza, other ethnic populations.
5,14,20
In 2002, two independent retrospective
immune reconstitution syndrome, concomitant viral infections and
other drug-related hypersensitivities (especially non-NRTIs). As a result,
Jürgen K Rockstroh is Professor of Medicine at the University
abacavir hypersensitivity may be incorrectly diagnosed
4
and the drug
of Bonn, and has been Head of the Outpatient Clinic since
unnecessarily discontinued. However, pharmacogenetic screening to 1995. He has recently been elected Chair of the German AIDS
identify patients predisposed to abacavir hypersensitivity is proving to be a
Society. His research covers a wide range of AIDS-related
topics, and in 2005 he was awarded the German AIDS Prize
promising approach to reducing the incidence of HSRs and improving the
from the German Society of Infectious Diseases for his study
safety of abacavir use. The major histocompatability complex (MHC)
on the effects of antiretroviral therapy on liver-related
mortality in patients with HIV/hepatitis C virus co-infection.
class I allele HLA-B*5701 has been established as a risk factor for
abacavir hypersensitivity
5–7
and is now the most extensively studied
pharmacogenetic marker in HIV therapeutics. Studies have convincingly Phillip E Hay is a Reader in Genito-urinary Medicine and HIV
demonstrated that screening for this allele in patients before commencing
at St George’s, University of London. He is Clinical Director
of the Courtyard Clinic, which cares for more than 1,100
abacavir therapy significantly reduces the incidence of confirmed HSR
8,9
HIV-infected adults. In addition to unselected HIV clinics, he
and, as such, the revised EACS (2007) guidelines recommend HLA-B*5701
runs the mother and baby clinic and participates in the
family clinic. He also leads the clinical trials team, and his
screening for all HIV infected patients on their initial assessment.
3
particular research interests include antiretroviral therapy,
diagnostics, bacterial vaginosis and infections in pregnant
Abacavir Hypersensitivity
women and Chlamydia trachomatis.
David A Leather is Medical Director of the GlaxoSmithKline
Hypersensitivity Reactions
(GSK) HIV Centre of Excellence, which is based in London.
While abacavir is generally well tolerated, approximately 5–9% of abacavir-
An experienced physician, he leads the team responsible for
treated patients develop the well-defined idiosyncratic HSR.
6,10–14
However,
planning and implementing GSK’s phase IIIb and phase IV
studies across Europe, including the PREDICT-1 trial.
the true basal incidence is difficult to establish as inter-study variability is
high
10
due to the influence of certain patient characteristics, in particular
E: david.a.leather@gsk.com
ethnicity, with rates being significantly higher in Caucasians than in patients
of African descent.
5,14
Symptoms usually develop early on in therapy – the
© TOUCH BRIEFINGS 2007 27
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