A new test that may predict if we will react badly to abacavir,
a widely used HIV drug, provides a glimpse into the future of HIV therapy
Words Robert Fieldhouse
Image C(Aitch)
An
emerging science called pharmacogenetics holds the promise of personalised
medical care for all. It will determine how our genes affect the way we respond
to medicines, to maximise their efficacy and improve their safety. Pharmacogenetics
is important for HIV because therapy is long-term, used in combination with
other antiretrovirals, and many people experience short and long-term side
effects.
Pharmacogenetics has little impact today and advances are unlikely to revolutionise
medicine in the near future. But one diagnostic genetic test for the HIV drug
abacavir (Ziagen) is already here and similar tests for other drugs are likely
to become routine in the next ten to 20 years.
New genetic test available
The HLA-B*5701 genetic test is becoming increasingly available in the UK.
It identifies whether we have a particular genetic variation that may increase
our chance of developing a severe, potentially life-threatening, allergic
reaction to abacavir. The London HIV Consortium agreed to pay for the test
for anyone in the capital starting or thinking of switching to an abacavir-containing
regime, and it’s now used in a number of London centres.
How will this test affect HIV care?
It remains to be seen whether all UK treatment centres will take up the test.
Some have offered it to patients since last year, even though medical experts
want more information about its sensitivity. When the Royal Society of Medicine
discussed the HLA-B*5701 test in a recent report*, it
concluded that the clinical use of the drug and the diagnostic test need to
be validated by large clinical trials.
The test has not yet been clinically validated in a large, diverse group of
people living with HIV, though it has been studied in a small but ethnically
diverse group of people living with HIV in Brighton. Without clinical validation,
some fear the test will fail to predict the abacavir hypersensitivity reaction,
also known as HSR, in a diverse population of people living with HIV taking
abacavir.
GlaxoSmithKline (GSK), who make abacavir, are planning a study of 2,000 people
worldwide. Half will start treatment with abacavir without taking the HLA-B*5701
test. The remainder will take the test and not start abacavir should they
test positive. Patch testing will be used to confirm the abacavir hypersensitivity
reaction.
When is it used?
Abacavir and its co-formulations Kivexa
(abacavir/3TC) and Trizivir (abacavir/3TC/AZT) belong to a family of drugs
called nucleoside analogues. Drugs from this class are the
‘backbone' of HIV therapy. Most people on treatments will be prescribed
one of three available dual nucleoside analogue co-formulations. These are:
Combivir (AZT, 3TC), Kivexa
(abacavir, 3TC) and Truvada (tenofovir, FTC). Some centres offer the test
before starting
people on an abacavir-based pill.
Dr Steve Taylor, lead consultant for HIV Services at Heartlands Hospital,
Birmingham, told PN: "We've been offering the [HLA-B*5701] test for around
six months now to non-black people nearing treatment for whom abacavir would
be an option."
All about Abacavir
Abacavir is a potent, generally well-tolerated drug. Typically, people who
get through the first six weeks on it find it simple to take and tolerate.
Abacavir's contribution to body fat changes is thought to be fairly negligible.
Currently there are only clinical trials demonstrating the effectiveness of
Kivexa (abacavir/3TC) lasting for up to 48 weeks, and longer-term data on
its safety and efficacy both from clinical trials and experience in the clinic
are needed.
Is this all about money?
For the first time last year the HIV treatment guidelines developed by the
British HIV Association (BHIVA) mentioned the cost of different antiretroviral
drugs, suggesting that some clinics may consider cost when selecting our HIV
treatment. Its latest audit of UK HIV treatment centres found over half took
cost into account when selecting antiretroviral therapies.
But cost should not be something a patient needs to consider. You should be
able to take the meds most likely to work for you in a combo you tolerate
best and that fits with your lifestyle.
False economy?
Researchers from the British Columbia Centre for Excellence in HIV/Aids, Canada,
recently challenged the notion that prescribing cheaper drugs actually saved
money.
They argued that discontinuing abacavir was fairly common; 12 per cent of
their patients did so within three months of starting. Mostly, this was due
to concern about development of the abacavir hypersensitivity reaction. They
showed patients who discontinued abacavir actually ended up costing the clinic
more as they needed to visit the doctor more frequently or seek emergency
specialist care. They argued that discontinuing abacavir in the first three
months meant patients took longer to get an undetectable viral load. Getting
undetectable in the first six months of treatment is associated with better
long-term outcomes.
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What
is the hypersensitivity reaction?
Until now we have relied on our doctors' clinical judgement to spot the signs
and symptoms of abacavir hypersensitivity reaction (HSR). HSR can be pretty
non-specific, making it hard to diagnose. Around 80 per cent of people who
develop it get a fever, two thirds develop a rash. Around half feel very tired
and complain of stomach problems such as nausea, vomiting, diarrhoea and stomach
pain. Around one in five get respiratory symptoms such as shortness of breath.
Occasionally, people develop joint pain or swollen glands. On average it takes
around 11 days of treatment with abacavir for HSR to develop, with the reaction
typically occurring in the first six weeks of treatment. However, for one
in ten people who develop the hypersensitivity reaction, symptoms don’t
develop until after ten weeks of treatment with the drug.
Globally, 31 people have died as a result of abacavir HSR. Most deaths occurred
before 2004, when people who developed it restarted the drug. People who develop
the reaction can never use abacavir again. Symptoms are normally progressive,
worsening with each dose.
How
useful is the test?
Typically, the abacavir hypersensitivity reaction occurs in around five per
cent of patients, though in some studies the suspected rate is eight or nine
per cent. A recent review of abacavir HSR by the FDA (Food and Drug Adminstration)
in the USA suggests there is an increase in both the HSR rate and severity
of the hypersensitivity reaction if abacavir is taken once-daily. The HSR
rate reported in earlier studies tended to be among people prescribed abacavir
twice-daily.
Last year a study in 50 people who used abacavir soon after acquiring HIV
reported that 18 per cent were suspected of having developed HSR. Nine were
suspected of developing hypersensitivity to abacavir, but only two were positive
for the HLA-B*5701 genetic variation, which caused the researchers to question
the test's usefulness.
Two years ago a native American with HIV in Canada developed the potentially
life-threatening reaction after taking a single dose of abacavir. He developed
symptoms within 30 minutes of taking it and was rushed to intensive care.
The drug was stopped and he made a full recovery. The HLA-B*5701 genetic test
revealed he did not have the genetic variation associated with HSR.
What is the background to the test?
Four years ago, two articles were published which linked the gene variant
HLA-B*5701 to development of hypersensitivity reactions. The larger GSK study
found the variant in 55 per cent of white people who had experienced HSR but
only one per cent of people were considered intolerant of abacavir.
HLA-B*5701 was absent in all nine black patients and in only one of the ten
Hispanic patients who experienced the adverse reaction. Therefore, many people
without the genetic variant still experienced HSR, leading researchers to
conclude that clinical monitoring for symptoms in people on abacavir should
not change.
It was Professor Simon Mallal, director of the Centre for Clinical Immunology
and Biomedical Statistics in Perth, Australia, who first identified the link
between HSR and HLA-B*5701.
In 2001 he tested his patients and found only two per cent with HLA-B*5701
did not develop a hypersensitivity reaction. However, one in four patients
testing negative for HLA-B*5701 still developed a hypersensitivity reaction.
Professor Mallal concluded that it could not be regarded as a screening test,
just that in a small number of white HIV positive people from Perth on antiretroviral
therapy including abacavir, the HLA-B*5701 was highly predictive of the hypersensitivity
reaction.
What exactly is HLA-B*5701?
HLA stands for human leukocyte antigen; genes involved in the development
of an immune response. They help the body identify foreign invaders, signalling
to another part of the immune system when something is wrong and triggering
an immune response. There are some well recognised associations between HLA
genetic markers and some inflammatory diseases (HLA-B27 and rheumatoid arthritis
for example).
A skin ‘patch test' is used to confirm a positive result on the HLA-B*5701
blood test. Different strengths of abacavir are dissolved in petroleum jelly
and applied to the skin which is covered with a small
plaster. The principle is that if you are allergic you will develop skin inflammation
in the next 24-48 hours.
However, it is possible any reaction could be due to the components of the
patch material or the sugar or glycol in the liquid formulation. We also have
to remember that some of us simply don't react through the skin if we are
allergic. If we did, everyone who develops an allergy to a drug would develop
a rash.
Genetic variation by ethnicity
The HLA-B*5701 genetic variation appears to be more common in white people
than
people of black African origin. Latest research by Dr Martin Fisher at the
Claude Nicol Centre, Brighton, revealed a higher-than-expected level of HLA-B*5701
in both groups. This evidence may be the most substantial we currently have
in an ethnically diverse population, but the Brighton population does not
accurately reflect the population seen for care in London HIV clinics, and
the sample size was fairly small.
Researchers tested 271 patients and found ten per cent positive for HLA-B*5701
(13 per cent among white patients and seven per cent among blacks). Previous
research had suggested the variation is uncommon among black people, but perhaps
this is not the case, only a larger study could provide more definitive information.
After taking the test, 81 patients who tested negative decided to initiate
treatment with abacavir. No hypersensitivity reactions have been seen in these
patients up to six weeks after starting the drug.
Dr Steve Taylor told PN the HLA-B*5701 test was not routinely offered to black
patients at Heartlands, and Brighton data had not changed this.
“At the moment we are unclear how to interpret positive/negative results
in these individuals. We are awaiting further data," he added.
A patient perspective
After two years on Combivir, Andi Morgan, 36 (pictured above), switched to
abacavir-containing Kivexa two months ago following an article in PN about
fat returning after drug switching.
“After a week on Kivexa I started to get really lethargic, developed
pain in my back, shoulders and neck, and had general flu-like symptoms such
as running nose, sore throat and headaches. My clinic told me to continue
with Kivexa”.
Before switching to Kivexa, Andi underwent a HLA-B*5701 test which came back
negative. This meant his symptoms were unlikely to be related to the abacavir
hypersensitivity reaction.
“I was told a very small percentage of people who take abacavir can
experience the reaction and it was potentially life-threatening. The doctor
warned me that a negative result could not guarantee I was not hypersensitive”.
Because the symptoms of HSR are so varied, it is very important to stay in
regular contact with your clinic if you are taking abacavir and develop any
of the symptoms described above.
The bigger picture
Clearly a test that can identify those genetically predisposed to a severe
drug reaction is welcome. But doctors and patients should remain vigilant
for signs and symptoms and use their clinical judgement as well as the test
results to ensure nobody hypersensitive to abacavir fails to be identified.
This new test should give more power to the patient to choose appropriate
treatment. No drug is suitable for everyone and a major strength of the UK's
approach to HIV treatment has been the assertion of the importance of individualised
care.
Your choice of treatment is a decision reached between you and your doctor,
using your treatment history and the results of HIV drug resistance testing.
Dr Taylor told PN: “We will continue to individualise patient care and
treatment as dictated by patient needs."
It would be foolish not to acknowledge the bigger picture. With more patients
diagnosed every year needing treatment, and people looking forward to a long,
healthy life on treatment, the NHS budget is under an increasing strain. Cost
savings may be something we all have to get used to.
Dr Taylor said: “If we move to a national tariff for HIV care in which
we have set monies to treat patients then I think it will be down to individual
clinics how they think to best use finite funding. This may include genetic
tests."
Let’s hope this won’t mean big pharmas have less incentive to
develop new drugs out of a fear that they will not be funded by the NHS.
• www.hiv-pharmacogenomics.org
• www.bpc2006.org,
for details of the 2006 British Pharmaceutical conference
* Personalised Medical Healthcare: hopes and realities, RSM, www.royalsoc.ac.uk/displaypagedoc.asp?id=15874
