HIV Genotype testing is the application of DNA sequencing technology to reveal the
genetic sequence of an individuals HIV strains. This insight can be extremely
valuable because specific mutations are associated with HIV resistance to specific drugs;
using this technology, physicians may soon be able to ensure maximum durable patient
response to treatment.
Two genotype testing methods are currently available: one sequences the entire genome
of HIV; the other looks only for "point mutations" at residues, or specific
sites on the HIV genome that are known to confer resistance to various HIV drugs. Although
genotypic testing has been used in clinical trials, it has not been widely used outside
these trials because of the difficulty in interpreting results generated by each assay.
Now F. Hoffmann - La Roche Ltd of Basel, Switzerland, has joined forces with Virology
Networks of Utrecht, The Netherlands, and PE Biosystems of Foster City, California, to
make genotyping a valuable tool for optimizing and individualizing HIV therapy.
A Hypothetical Case Study for the Future Management of an HIV-Infected Person
Sarah, 32 years old, was diagnosed HIV-positive four years ago. She has been
taking a three-drug, protease inhibitor-containing treatment regimen since her diagnosis;
one of the drugs she is taking is AZT (an NRTI). Having heard that HIV can mutate easily,
Sarah is very careful to take her medication every day at the appropriate times. While she
has responded well to treatment, her HIV viral load, previously undetectable, has begun to
Sarahs doctor, curious as to why the regimen seems
to be losing its effectiveness, orders a genotype test run on her blood. The results show
a mutation at codons 41 and 215 on the RT gene.
Sarahs doctor then consults the RetroGramTM
decision support software to provide an interpretation of the significance of these
mutations. The program indicates that these mutations confer resistance to AZT, indicating
that this drug is unlikely to continue being a useful component of Sarahs treatment
He decides, in the absence of any other known mutations
to the other drugs she is taking, that he will switch Sarah from AZT to another drug in
the same class; they agree that she will continue to take the other two drugs, and
hell conduct another viral load test in six weeks.
Why Its Important
As seen in the example above, HIV genotype testing has the potential to give doctors
and patients unprecedented insight into any mutations present in an individuals HIV
genome. Armed with this knowledge, physicians could make treatment decisions to maximize
the impact of anti-HIV drugs. In two examples of this approach, preliminary data from the
VIRADAPT study in France and the GART study in the USA show that knowing the genetic
sequence of the HIV quasi-species can provide information with real clinical significance.
These data are important for rational drug selection when assembling a combination regimen
in at least four important patient populations:
- those choosing first-line therapy, specifically in the increasingly common context of
mono- or multi-drug-resistant HIV being transmitted
- those whose therapy is now beginning to fail, who need to consider changing their
- those needing post-exposure prophylaxis, especially in a clinical setting where AZT
resistance is becoming more prevalent, and
- pregnant women, especially in the context of a failing regimen since studies have shown
that viral load at delivery is the main correlate of vertical transmission.
The GREAT Trial
To put genotype data into the hands of practicing physicians in an understandable and
clinically useful way, Roche is partnering with Virology Networks and PE Biosystems to
sponsor a prospective clinical trial called GREAT -- Genotypic Resistance Evaluation to
Aid Therapy-switching. GREAT will evaluate the benefit of resistance testing in the HIV
treatment setting and will include a variety of different treatment approaches and a wide
range of anti-HIV medications. The trials purpose is to explore the clinical impact
of applying a sequencing-based genotyping method, the recently launched PE
Biosystems HIV Genotyping System, and to test a rules-based software algorithm that
ultimately will provide information to support treatment decisions.
GREAT is a randomized, international, parallel-group, open-label, 48-week trial
enrolling up to 360 patients who are currently failing their first-line protease
inhibitor-based anti-HIV combination regimens; failure is defined by at least 24
consecutive weeks' experience with a PI-containing combination regimen and a viral load of
at least 5,000 copies/ml (or 3.7 log10) at screening. Participants will be
randomized to a new regimen by one of two methods: either best clinical judgment or best
clinical judgment in conjunction with real-time HIV resistance genotyping.
The GREAT trial also will test the prototype RetroGram Decision Support Software. This
experimental software, designed jointly by Virology Networks and Roche and developed by
UK-based decision support specialists InferMed, uses an electronic rule-based algorithm to
interpret genotype data and guide physicians and patients in treatment decisions.
Roche and Virology Networks believe that by creating and validating such software to
interpret the results of genotype testing, they will provide a clinically
useful tool to physicians and patients. This would represent an advance in rational
combination drug regimen design, hopefully maximizing individuals' therapeutic options
over the long term.
"From Roches perspective, we are trying to redefine the way pharmaceutical
companies approach the development and marketing of drugs in this disease area. We want to
drive the best use of our drugs by understanding when they should be used and, more
importantly, when they should not. If we can do this, we can offer unprecedented value for
physicians, we can increase the value of our therapies to patients, and we can heighten
the intrinsic value of our franchise," said Martin Hangarter, Ph.D., Roches
Business Director for Virology and Infectious Diseases.
Although Roche is providing significant support to the GREAT study, the trial has been
designed to include the entire armamentarium of approved HIV treatments. This will ensure
that the GREAT data are thorough, accurate, impartial, and applicable to the broadest
array of patients in the real world. Virology Networks, together with an expert panel of
investigators, will interpret new information to refine the rules governing the software
on an ongoing basis. This will allow the software to incorporate each patients
experience to generate rules that reflect real-world experiences.
"Roche has purposely left this component of the program in the hands of Virology
Networks and an independent expert panel that will interpret the data separate from of any
pharmaceutical company. We believe that this approach -- one that provides independent
confirmation of the value of our medications and others -- will best serve the
physician and the patient," said Dr. Hangarter.
An Evolving Field
While the tests have been shown to be accurate and reliable, the role of genotyping in
the clinical setting is still evolving. There is some disagreement among scientists about
what a particular result actually means in terms of treatment decisions.
Because genotype tests characterize only a representative sampling of the quasi-species
of HIV present in a particular individual, the validity of the tests is questionable if an
individuals viral load is below 1,000 copies/ml. Clinicians should
use genotypic testing in conjunction with viral load assessments and prior treatment
history in making treatment decisions.
Another concern is that these tests show only what resistance might occur, not which
drugs will work -- they cannot guarantee the success of a particular regimen.
Like HIV RNA viral load tests before it, HIV genotype testing is a novel approach that
requires refinement and testing to ensure that the information it provides is used to
maximize results for the patient. The use of PE Biosystems HIV Genotyping System
will provide greater standardization across participating laboratories, will simplify and
accelerate the data assessment, and will minimize variables that might exist in the
absence of standardized methodology. As with genotype testing, results will help
physicians make more informed therapeutic decisions. Testing does not replace a
physician's clinical judgment, but serves to enhance it.
By adding this new technology to the HIV armamentarium, physicians and patients can
move one step closer to keeping HIV down for the long term.
1 Durant J, Clevenbergh P, Halfon P, Delgiudice P, Porsin
S, Simoner P, Montagne N, Dohin E, Dellamonice P. Can HIV genotype determination be useful
for individualized adaptation of antiretroviral therapy: The VIRADAPT French Study. 4th
International Congress on Drug Therapy in HIV Infection. 8-12 November 1998, Glasgow, UK.
2 Hirsch MS et al. Consensus Statement:
Antiretroviral Drug Resistance Testing in Adults with HIV Infection: Implications for
Clinical Management. JAMA 279/24 (June 24, 1998):1984-1991.