Mapping Out Your Treatment
Journey
A look at resistance testing
by Frank Pizzoli
If you don’t know where
you’re going, any road will take you there.
Sixteen anti-HIV drugs are
now available. Another dozen agents are projected for review
by the Food and Drug Administration (FDA) in the next several
years. Beginning or maintaining HAART (highly active anti-retroviral
therapy) is a journey made less risky–but not risk free–with
advances in genotype (GT) and phenotype (PT) resistance tests.
Not yet FDA approved, these
tests can potentially identify drug regimens that would be
more effective for a particular person. The idea is to establish
a “sequencing” of drugs in order to maximize available
drugs’ anti-HIV qualities and prolong treatment benefits
for as long as possible. While test results are useful, neither
test can tell with certainty who will gain most benefit from
particular drug combinations.
Genotype testing determines
any changes, called mutations, to the part of HIV’s genetic
structure that makes key proteins. Viral samples are inspected
for the presence of specific viral mutations known to be resistant
to certain drugs. The reverse transcriptase gene is the target
for nucleoside analogs (Hivid, Videx, Zerit, Epivir, Ziagen,
and Retrovir, or AZT) and non-nucleoside analogs (Rescriptor,
Sustiva, and Viramune). The protease genes are attacked by
protease inhibitors (Agenerase, Crixivan, Fortovase, Invirase,
Norvir, and Viracept).
Just beginning
Individuals
beginning HAART face challenging decisions: to begin with
or delay the use of protease inhibitors or non-nucleosides,
or both. Resistance testing might be especially useful in
helping individuals identify if their viral type is responsive
or resistant to PIs or NNRTIs, and which ones.
Resistance
tests also help individuals identify if they have been infected
with a virus already resistant to antiretrovirals. The possibility
for this is higher in cities like New York or San Francisco
where many people have been treated extensively, and may therefore
be shedding a “mutated” virus. Resistance tests
can be done before treatment starts to avoid using drugs that
are unlikely to be effective.
Likewise,
with needlestick exposure or possible maternal transmission,
the virus may be tested to ensure it is not already resistant
to certain drugs. Of course, treatment may need to begin before
test results are available.
Although
these tests may help with treatment decisions, individuals
must carefully compare their own HIV history and characteristics
with known treatment outcomes. For example, results from Merck
Study 035 indicate that success with PIs in first-line treatment
is durable: 30 patients received Retrovir (AZT) with Epivir
and the company’s protease inhibitor Crixivan for three
years, and 20 of the 30 still have a viral load below 50 copies.
Another
study concluded that PI-containing regimens “had a greater
effect on the lymph nodes than those containing nucleoside
analogs alone despite comparable levels of suppression”
of HIV. Although these regimens are durable for study participants,
this combination may not be able to fight down all viral types,
making resistance testing an attractive choice.
Other
results show that individuals on PIs may have HIV levels rebound
after achieving undetectable viral loads, but that this virus
causes less immune destruction. This explains why individuals
whose viral load rebounds on PIs do not always experience
declining CD4 cell counts. Individuals whose resistance tests
indicate PI effectiveness may want to begin with a PI combination,
hoping to diminish the virus’s strength over time.
Although
many clinicians consider PIs optimal first-line therapy, it
is possible to lower viral load without their use. If an individual’s
unique HIV genetic code isn’t resistant to non-PI drug
combinations, a protease-sparing regimen may be useful in
controlling viral load. This approach saves PIs for future
use, if and when individuals become resistant to an initial
drug combination.
Phenotype
resistance is a more direct measure of viral resistance to
specific HIV drugs. It examines the amount of drug needed
to inhibit HIV growth. In its natural state, HIV is a “wild
type virus” and is usually not resistant to particular
HIV drugs. This allows them to suppress replication of the
virus. Resistant virus requires higher levels of existing
drugs to achieve an equal amount of suppression.
Both
tests identify genetic HIV sequences in individuals’
blood samples and then compares them to a “registry”
that holds the “true” genetic HIV sequence. Deviations
from the “true” sequence correspond to resistance
to certain HIV drugs. Knowing these differences is important
information when people begin treatment or for those whose
drug combination has become resistant to their regimen. In
a perfect world, people would combine GT to establish the
specific “type” of virus in their blood with PT
to determine the effective “amount” of particular
anti-HIV drugs they need to take.
Experienced individuals
In several retrospective studies
(looking back at what happened) of treatment-experienced people,
baseline GT and PT results predicted response to new therapy.
Although prospective studies are still needed, these results
begin to validate the tests’ usefulness. For example,
when a combination treatment fails to control the virus, a
resistance test may help decide what new combination might
work. In this scenario, the test must be done while the patient
is still taking the failing drugs, since without the drugs
resistant virus is likely to be replaced by the original non-resistant
virus. It then declines to very low levels that the tests
will not detect. Yet, the virus will be ready to come back
almost immediately if the drug is started again.
Keep in mind that recent studies
suggest that PI resistance may not be an issue for individuals
who experience viral rebound while on PI-containing regimens.
The predominant virus that rebounds is often resistant to
the other drugs in the combination, but not the PI. In this
case the other drugs can be switched or another drug added
as an attempt at therapy “intensification.” This
is a classic example of how resistance testing might be used
to identify and monitor particular drug sequences.
The next round
People with drug resistance
have a lot of variables to wrestle with. For example, someone
is taking all their drugs on schedule and observing food requirements,
and yet the regimen has failed. Assuming that you are absorbing
enough of the drug to get an effective level in the body,
the most likely cause of drug failure is anti-retroviral resistance.
If resistant, the “next
round” of drugs will depend heavily on previous drug
exposure and likely include a PI or two, and an NNRTI, or
both. Several studies show success with the inclusion of an
NNRTI in subsequent regimens, especially if someone has never
taken an NNRTI. For example, one study showed that these people
achieve lower HIV viral loads at 24 weeks than do patients
who have previously used an NNRTI. The small sample also indicated
that 83% of the NNRTI-naive individuals see a 0.5 log decrease
in viral load while only 66% of NNRTI-experienced people see
the same result. The use of more PI-sparing regimens as first-line
HAART may allow for NNRTI-naive individuals to have a reasonable
chance at treatment success when searching for the next combination.
Please note that NNRTIs originally
were thought by most to have less antiviral potency and durability
when compared with the PIs. On-going trials are calling into
question those assumptions. The DuPont 006 study now has 48-week
data showing that patients who start with high viral loads
(over 100,000 copies) can have sustained viral suppression
on a protease-sparing regimen of the company’s non-nucleoside
analog drug Sustiva in combination with AZT/Epivir. Consequently,
resistance testing may be vital for individuals whose drug
treatment plan is failing in order to properly identify remaining
drug combination choices.
Because individual reactions
and resistance to various drug regimens vary widely, physicians
familiar with the tests warn that using the tests to identify
remaining useful anti-HIV drugs is best done “sooner”
than “later.”
Pros and cons
GT is a less complex, less
expensive test ($300—$500 per test) with results more
rapidly available. Beware that some mutations counteract each
other, so results may not be able to truly determine drug
resistance. For drug-resistant individuals who have stopped
therapy, GT may still be able to identify mutant virus. This
test may be more accurate for nucleoside analogs and non-nucleoside
analogs, and less useful for PIs that do not always show consistent
mutation patterns. For accurate GT results, viral load must
be above 1,000 copies.
PT is a more complex, more
expensive test ($800—$1,000) with results taking longer
than GT. On the plus side, HIV mutations are generally interpretable
for all anti-HIV drugs. PT results work best with a viral
load of 5,000 copies.
So, resistance testing
can be used either to select the best initial therapy or to
realign existing therapy. When you decide you’re ready
to rumble with HIV, perhaps GT and PT may help you go a few
extra rounds in the ring.
Freelance writer
Frank Pizzoli is founder and executive director of Positive
Opportunities in Harrisburg, Pennsylvania, an HIV-employment
service where drug choices, effectiveness and adherence really
matter. E-mail fpizzoli@aol.com
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