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The Buzz:
Viread, Epivir and Ziagen Combination—Failure in Naïve
Patients With a Once-Daily Regimen
by Daniel S. Berger, MD
Since the first release of the drugs, abacavir
(Ziagen) and tenofovir DF (Viread), scientists and researchers
were caught in a quandary. What seemed at the outset like
a no-brainer, administering two very potent and promising
agents in combination once-daily, should have resulted in
satisfactory results. This was not the case.
What happened? The FDA approved abacavir
to be administered twice daily. Later, some pharmacokinetic
studies suggested that one could potentially take this drug
once-a-day. A clinical study, though preliminary, presented
last year in Buenos Aires, added to the fuel. Thus a GlaxoSmithKline
(GSK) sponosored study, ESS30009, was designed to look at
a “fixed dose tablet” or “Easy Tablet”,
that is, a new formulation of 3TC (Epivir) and abacavir in
one pill and to be administered once daily. The study compared
Epivir + Ziagen + Viread against another regimen of Epivir
+ Ziagen fixed tablet + efavirenz (Sustiva) with all regimens
dosed once daily. As a principle investigator in this study,
I found the protocol to be of interest, especially in light
of data showing both Ziagen and Viread as being quite potent.
In another study, the potency of Viread was compared with
the protease inhibitor, ritonavir (Norvir); preliminary work
with Ziagen monotherapy also showed it to be a strong and
potent agent.
In study ESS30009, investigators knowing
full well what regimen their patients were randomly assigned
to (being open-label) soon observed obvious differences between
the regimens. Our clinic, Northstar Healthcare in Chicago,
enrolled 14 patients in this study, six of whom were on the
Viread regimen and eight patients on the Sustiva based regimen;
nine of whom have reached between 8 and 16 weeks. In the global
study 345 patients were randomized and only 125 individuals
had reached 12 weeks. At this early point differences in the
study arms were already being observed, which forced an early
interim analysis.
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Their letters described
that a substantial number of patients on the Epivir +
Ziagen + Viread regimen were failing.
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Thus, in mid July, principle investigators
received urgent communications from GSK. So, as soon as the
early indications emerged, GSK sought to notify the unexpected
results to their investigators, however disconcerting. Their
letters described that a substantial number of patients on
the Epivir + Ziagen + Viread regimen were failing and recommended
that our clinical judgment and practice should take steps
to ensure the best possible care of our individual patients.
This meant that if our judgment dictated withdrawing certain
individuals from the study, then this should be done. Additionally,
talking with scientists at Gilead Sciences, makers of Viread,
it was obvious they were also working diligently in investigating
the cause for these outcomes.
Analysis of the data
The letter to physicians from GlaxoSmithKline
provided the following: Of 102 individuals ramdomized, 50
subjects or 49% who were on the fixed dose of Ziagen/Epivir
in combination with Viread with at least 8 weeks of viral
load data (HIV-RNA) demonstrated “non-response.”
Non-response means those individuals failed to achieve viral
load drops greater than 2 logs or were already showing increases
in viral load from their previous visit values. This compared
with only 5/92 patients or 5.4% randomized to the Ziagen/Epivir
+ Sustiva combination. Looking at the data in fewer patients
but at 12 weeks, again the results were similar. 30/63 patients
or 47.6% on the Ziagen/Epivir + Viread arm were non-responders
vs. 3/62 or 4.8% on the Ziagen/Epivir + Sustiva arm.
Although this analysis was carried out
at an early juncture of the study, the results were of much
concern. Under normal circumstances with effective
regimens, this phenomenon of high “non-responders”
should not normally be observed.
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It may be that once-daily
doses of Ziagen and Epivir may not be enough throughout
a 24-hour period to maintain enough supression and pressure
on HIV.
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This in concert with another study reported
at the International AIDS Society meeting in Paris during
July only confirmed and intensified the implications. Dr.
Charles Farthing from Los Angeles studied 20 patients also
naïve to antiviral treatment. The subjects were placed
on a once-daily regimen of the same agents, Ziagen, Epivir
and Viread. Nine of 17 patients (52%) had viral load rebound.
These patients were adherent to their regimen based on “pill
count” during their follow-up visits.
Possible explanations and hypotheses
It is worthy to note that Gilead Sciences
has conducted its own studies on the pharmacokinetic interactions
of both drugs, finding that neither agent significantly compromised
blood levels of the other.
Dr. Michael Miller, Director of Clinical
Virology at Gilead Sciences, says two principle possibilities
may explain the regimen’s poor potency. First, it is
possible that an intracellular interaction between Ziagen
and Viread may be occurring and lowering drug levels in cells.
Second, resistance to the drugs themselves may be at fault.
Whatever the reason, patients being administered these agents
“once-daily” may only be exacerbating the manifestations
of the problem. If, however, resistance was the start of the
problem or primarily at fault, one would expect more complete
resistance mutations in those failing patients. In Dr. Farthing’s
cohort the Epivir-associated M184V mutation was observed in
many failure patients, the K65R was seen in only half of the
failures. Thus complete resistance occurred in relatively
too few patients and does not explain the observation of high
levels of failure; in general, I believe that the presence
of K65R as the sole mutation is not as common, nor significant
enough cause for individuals to completely fail their regimens
clinically.
Moreover, resistance mutations can often
be due to one of several causes including non-adherence, not
enough antiviral penetration into body compartments, or not
enough blood levels of drug. And it may be that once-daily
doses of Ziagen and Epivir may not be enough throughout a
24-hour period to maintain enough suppression and pressure
on HIV in some select patients. Recently in the ACTG 5095
study (see “The
Buzz” May/June 2003) we saw another triple nucleoside
regimen, Trizivir, also demonstrate lower potency compared
to a Sustiva based regimen. Although this particular drug
regimen of Trizivir was twice daily we may be receiving the
same message: triple nucleoside regimens are not consistently
effective as non-nuke or protease inhibitor based regimens—clinician
beware.
However, many argue that there is a place
for triple nucleoside therapy, particularly for individuals
without a heavily compromised immune function. Alternatively,
one should remember that resistance occurs usually after having
responded initially to treatment. The fact that many patients
in ESS30009 did not respond from the get-go leads one to consider
possible drug interactions. Researchers at Gilead Sciences
note that various other studies are ongoing in which Viread
and Ziagen are being used successfully in combination. These
studies are not once-daily, triple nucleoside regimens, however.
Additionally other studies being sponsored by GlaxoSmithKline
using the once-daily abacavir-Epivir "Easy Tablet"
are also showing favorable response in other regimens.
Conclusion
It may be premature to invoke a rule of
not using these two drugs in combination in other clinical
scenarios at this time. Physicians should use their clinical
judgment in their individual patients. However for now, it
would be prudent for clinicians not to use these two agents
in a once-daily regimen, especially in naïve patients.
Furthermore, physicians should not initiate patients on a
once-daily regimen of Epivir, Ziagen and Viread. Both companies,
GSK and Gilead are aggressively pursuing the challenge of
identifying the direct cause of the problem with laboratory
and intracellular research. Patient care is paramount.
Daniel S. Berger, MD, is Medical Director
of Chicago’s largest private HIV treatment and research
center, NorthStar Healthcare, Clinical Assistant Professor
of Medicine at the University of Illinois at Chicago and editor
of AIDSInfosource (www.aidsinfosource.com).
He also serves as medical consultant and columnist for Positively
Aware. He has contributed to the recently released The
First Year—HIV, An Essential Guide for the Newly Diagnosed
(2003; Marlowe & Company, New York). Dr. Berger can be
reached at DSBergerMD@aol.com
or (773) 296-2400.
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