The Buzz:
Anatomy of a Study—Trizivir vs. Sustiva
by Daniel S. Berger, MD
Results of important
studies often become available when they are presented at
national and international conferences, this being well before
publication in a medical journal. Sometimes, however, the
study can be terminated with results of safety issues unveiled
even earlier. In other words, the study design can be changed
or terminated when there is a significant disparity in treatment
for a particular study arm; those study subjects may be taking
a significantly inferior treatment or one in which a significant
toxicity is more common. In this situation a letter is generally
sent to all the investigators of a study.
This is the case in a study
comparing Trizivir and Sustiva. In this instance a communication
was mailed to all HIV practitioners; investigators studying
Trizivir vs. Sustiva (efavirenz) felt there to be a significant
difference in effectiveness of one treatment arm and one inferior
arm was terminated. Let’s dissect the information to investigate
the possibility of any existing drama in ACTG A5095 (AIDS
Clinical Trials Group).
Background
Basically, this study compares
Trizivir against two Sustiva-based regimens. However, we have
already known the following facts regarding these two agents,
since they have been in use for quite some time and are considered
very basic knowledge by most savvy HIV specialists.
1) Using a Sustiva-based
regimen with two other drugs affects the virus from two vantage
points with two drug classes (non-nucleosides + nucleoside
background), as opposed to a single regimen comprised of Trizivir,
of which all three components are of the same nucleoside class
of drugs.
2) Sustiva is a very potent
agent and its effect has been compared to potent single (non-boosted)
protease inhibitors.
3) Durability of the effect
of Sustiva-based regimens are quite long, thus failure rates
are comparatively low.
4) Trizivir offers the benefit
of having three drugs combined into one pill; thus offering
the patient simplified administration, thought to improve
adherence.
5) Patients with very advanced
disease should initially be started on a more potent regimen
than Trizivir alone, since they are more at risk for treatment
failure.
6) Trizivir can be used as
a component of other regimens; it easily adds potency without
unduly increasing the pill burden.
Details and Results of
ACTG A5095
All study participants of
ACTG A5095 were naïve to antiviral medications (having no
experience on any antiviral meds previously); their antiviral
treatment arm was chosen at random in a double blinded manner
(neither physician nor patient would know which regimen the
patient was taking). There was not a CD4 count criteria for
entrance into this trial. The study participants were to receive
either
- Trizivir + Sustiva placebo (sugar
pill),
- or Combivir + Sustiva (efavirenz),
- or Trizivir + Sustiva
Trizivir consists of Retrovir
(AZT), Epivir (3TC) and Ziagen (abacavir). Combivir consists
of Retrovir and Epivir.
1,147 patients were followed
for an average of 32 weeks. The mean (average) CD4 T-cell
count at baseline (start of study) was 238 cells and HIV RNA
was 78,825. However, 43% of study patients had viral loads
greater than 100,000 copies vs. 57% had HIV RNA below 100,000
at start of study.
Since the National Institutes
of Health sponsors and funds all ACTG studies, they sent a
letter to physicians informing them of the interim results.
They reported that 21% of the patients on Trizivir only had
been considered virologic failures vs. 10% in the other two
groups (both Sustiva arms) combined. It is worthy to note
that this study considers and deems virologic failures for
viral loads greater than 200 copies at least four months after
starting treatment.
With these results in hand,
an independent panel, the Data Safety Monitoring Board (DSMB),
recommended stopping the Trizivir arm and is providing the
volunteers with the option of an alternative regimen, whether
they were failing (viral loads above 200 copies) or still
at undetectable levels. It is common to have an independent
panel of experts review studies during the ongoing trial,
they would intercede for the benefit of the patients. Additionally,
the remaining patients of the two other treatment arms who
were administered Sustiva were told they were taking Sustiva
but still blinded as to which nucleosides were their background
treatment.
According to sources familiar
with this study, 74% of patients randomized to Trizivir arm
and 89% of the pooled Sustiva arms still maintained viral
loads undetectable at an average at week 48 (Intent–to-Treat
analysis). Approximately 50% of patients had CD4 counts less
than 200 and the median CD4 count was 214 cells in this study.
In fact, 17% of patients randomized to the Trizivir arm and
20% in the pooled Sustiva arms had CD4 counts between 0-50
cells.
Issues Regarding Advanced
Disease Patients
One should understand that
all patients in this study had an equal chance of being randomized
to any of the three regimens, even when knowing that patients
who had either very low CD4 count or very high viral loads
before treatment, or at baseline, have an increased risk of
virologic failure. Moreover, there have been several studies
demonstrating that patients with viral loads greater than
100,000 would be better off with a quadruple regimen (two
protease inhibitors, for example) or one that contains Sustiva.
Particularly, another study,
DMP-006, was completed several years ago and ran for more
than three years. It was historically important because of
several significant findings and it led to the quick approval
of Sustiva by the FDA. Here patients were randomized to either
Sustiva or Crixivan, each with Combivir (vs. Crixivan + Sustiva
alone). Sustiva was shown to be superior over Crixivan, and
a sub-analysis in this trial demonstrated patients with CD4
count below 100 or high viral RNA at baseline were also successfully
treated with Sustiva.
Moreover, other studies showed
the benefit of administering dual protease inhibitor regimens
in these immune-suppressed patients as being more advantageous
for durability (longer time to treatment failure), than a
triple therapy regimen. With this in mind, many physicians
do not offer a simplified regimen of Trizivir for the patient
considered very advanced or in a late stage of disease.
One wonders the rationale
for designing a study that potentially places the immune-devastated
patient on Trizivir alone. Alternatively, the results of a
Sustiva-based treatment (not to mention a quadruple therapy
arm containing Sustiva) in this advanced disease population
beating out Trizivir was not a revelation nor a shock to us.
A Brief Summary Discussion
The results of this trial
should not be overlooked. One does not criticize this ACTG
study with its strict study design as being double-blinded
and placebo controlled. However, one notes that placing patients
in a blinded study, in which Trizivir randomized patients
are instructed to take their Sustiva placebo on an empty stomach
unfairly abolishes the real life advantage of one Trizivir
pill twice daily, with or without food. Also, uncertainty
does exist regarding the use of certain three- and four-drug
combinations utilizing specific drug classes, which may be
one of the questions that the ACTG intended to answer with
this trial. However, from a clinician’s experience, some things
remain as clear as before this study: Trizivir does have its
place in the HIV treatment armamentarium. Sustiva-based regimens
are very powerful. Also, for the advanced disease patient,
more potent regimens need to be considered so that those individuals
have a better chance of success with their first regimen.
Daniel S. Berger, MD,
is Medical Director of Chicago’s largest private HIV treatment
and research center, NorthStar Healthcare, and 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. Dr. Berger can be reached at DSBergerMD@aol.com
or (773) 296-2400.
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