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Special
International AIDS Society Section
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We Want Our Trizivir!
by Enid Vázquez
I’ve never seen so many
doctors so reluctant to accept the results of a clinical trial.
Everyone wanted so badly for Trizivir to show stellar results.
As three medications in one
tablet taken twice a day, Trizivir’s easy-to-take, easy-to-tolerate
profile makes it an attractive option (if you’re not
allergic to it). This is in spite of the fact that the three
medications in Trizivir (made by GlaxoSmithKline)—Retrovir
(AZT), Epivir (3TC) and Ziagen (abacavir)—are all in
the same drug class, nucleoside analogue, or nuke for short.
Usually, combination therapy consists of at least two of the
four drug classes on the market.
Here, when Trizivir was compared
to Trizivir plus Sustiva or Combivir plus Sustiva, people
on Trizivir alone had more virologic failure. As a result,
the Data and Safety Monitoring Board (DSMB) overseeing this
clinical trial, ACTG 5095, stopped the Trizivir arm of the
study early. (Combivir is made up of two of the three drugs
in Trizivir—Retrovir and Epivir.) But this clinical trial
was a little more complicated than it would seem, as Dr. Daniel
Berger explained in the May/June issue of Positively Aware
(see “The Buzz”).
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ACTG 5095
Dr. Roy M. Gulick of Cornell
University faced an onslaught of questions when he presented
the results of this study in Paris during the International
AIDS Society conference in July. ACTG 5095 was a large trial
of 1,200 people, 19% of them women, more than half of all
participants people of color (60%). (ACTG stands for AIDS
Clinical Trials Group.) All participants were treatment naïve—that
is, they were taking anti-HIV therapy for the first time.
The treatment naïve have the best results in clinical
trials, as do most people taking therapy for the first time.
Trizivir did worse at lowering
viral load whether or not people started with more or less
than 100,000. Twice as many people had virologic failure,
defined as going above 200 viral load twice at 16 weeks or
later, as compared to the Sustiva arms of the study (21% vs.
11%).
Moreover, the time to virologic
failure was shorter with Trizivir. For most of the Trizivir
failures, that was within four weeks. Looking at whether people
started out with more than 200 T-cells or less, the results
were the same. The simple conclusion of the study, not surprisingly,
was that, “In treatment-naïve patients, [Trizivir]
was inferior to [Sustiva]-containing treatment in terms of
rates and time to virologic failure.”
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Questions
One audience member pointed
out Trizivir’s advantages in simplicity, plus lack of
drug interactions and co-pays for other drugs. Another asked
about the clinical disadvantages of Trizivir for the 20% of
failures who didn’t have enough viral load to run a resistance
test (1,000). In other words, they still have relatively low
viral load and wouldn’t be expected to get sick.
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Gulick said that, “A
strict definition of virologic failure is needed in this study
to power the results [make them statistically relevant]. But
in the clinic you can use your judgment and look at what patients
want to do with the information.”
Another audience member raised
the question of drug resistance. If most people had the Epivir
signature mutation (M184V) at the time of first failure (before
the routine confirmation viral load test), doesn’t this
raise the issue of inadherence or of inaccurate reporting
of good adherence? Gulick said that 22% of failures had wild
type virus—indicating that those people took little or
no medicine. (Nevertheless, this would point to another glitch
in the Trizivir glamour—it’s supposed to lead to
better adherence, not worse, because it’s more convenient
to take.)
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Another audience member asked,
“Are we to give up Trizivir forever?” Gulick replied,
“Trizivir did have efficacy. If you look at other studies,
that can help you.”
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Yet another member of the
audience pointed out that because Sustiva was in two of the
three arms of the study, that the Sustiva arms actually had
half of the failures. “That’s worse, because you
fail two classes [of drugs]. Half the failure with double
the resistance is not so great.” Another doctor made
the same point after the presentation: when you have resistance
to Sustiva, you have resistance to the entire non-nucleoside
analog class of drugs. He called that “an expensive failure.”
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A Florida researcher said
that when clinical trial participants don’t have early
strong results in viral load drop, the clinic brings in those
participants and focuses on adherence, and “nine out
of 10 times, that’s the problem. The pill count is off.”
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One doctor pointed out that
because the study was placebo-controlled—so that everyone
took the same amount of pills in the same way—Trizivir’s
simplicity of only two pills a day was compromised. He said
Trizivir was studied “with one arm tied behind its back.”
Doctors also lamented the
loss of another advantage if they have to cut back on Trizivir
use—one co-pay for three drugs.
Perhaps the biggest question
raised: Is a three-nuke regimen really inferior? Gulick pointed
out that the remaining Sustiva arms of the trial have not
been unblinded. (Participants are still taking medicine in
a blinded fashion—neither they nor the clinic staff know
which regimen they’re on.) In other words, maybe Trizivir
with Sustiva will have better results than Combivir with Sustiva.
Nevertheless, Trizivir didn’t make it on its own.
Questions unsolved
There’s no question
that people are doing well on Trizivir. They can continue
their regimen with the same careful monitoring anyone else
should be getting while on HIV therapy. (They can also choose
to switch or intensify with another drug if they want.)
The question is, should anyone
be started on Trizivir as their first regimen? The answer
remains to be seen. So far, it may be that only people with
low viral loads should be started on it. In this trial, it
was recommended that even the people who were undetectable
with Trizivir add Sustiva, or that they switch out Trizivir
for Combivir and add Sustiva.
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