PI Perspective #18
April 1996 View PDF En
español
Update on Other Antivirals
Late in 1995, AIDS researchers reported the preliminary results
of two large long-term combination therapy studies. The U.S. ACTG
175 study and the European Delta study concluded that two drugs,
AZT + ddI or AZT + ddC, are superior to AZT alone. Both studies
show improvements in survival, not just on CD4+ counts and viral
load. More data are now available from these studies, and yet another
large long-term combination study has reported results. All three
studies are remarkably consistent in demonstrating that AZT monotherapy
should no longer be used as a standard of care. Data from recently
announced virology studies make it clearer than ever that single
drug therapy of any kind is not an adequate treatment for HIV disease.
AZT, ddI, ddC Combinations
Preliminary results have been released from the Community Programs
for Clinical Research on AIDS (CPCRA) study 007 (also known as the
NuCombo study). This was the last of the trio of large studies to
compare AZT, ddI, and ddC combinations to monotherapy. Results from
this study, in addition to further analysis of the previously reported
Delta study, confirm the benefit of AZT + ddI combination therapy.
The CPCRA study enrolled 1113 people with fewer than 200 CD4+ cells
or a prior AIDS diagnosis (254 of whom had never previously taken
antiretroviral therapy). Study participants received AZT, AZT +
ddI or AZT + ddC. At study’s end, there was no clear difference
between the three groups in time to disease progression or in survival.
However, a survival benefit was observed, after an extended follow-up,
for people on AZT + ddI compared to people receiving AZT alone.
This was especially true for people who had never previously taken
antiretroviral therapy.
Further analyses of the European/Australian Delta study show that
people who had never previously taken antiretroviral therapies and
received AZT + ddI in combination were less likely to progress to
disease compared to people receiving AZT + ddC or AZT alone. Among
people receiving AZT + ddI, those who were AZT-experienced gained
a survival advantage compared to those receiving AZT alone. (For
full results from ACTG 175 and Delta, please see PI
Perspective #17).
d4T and ddI Combination
Preliminary results from an ongoing ddI + d4T study demonstrate
that this combination has a positive effect on viral load and CD4+
cell counts. Ninety-four people with CD4+ cell counts of 200 to
500, who had not used previous antiretroviral therapies received
one of five different doses of the combination. On average across
all groups, they saw a 1.2 log drop in HIV RNA levels after 4 weeks,
which appears to be sustained after a year on the therapy. There
was an average 55 CD4+ cell rise after 4 weeks and after 52 weeks
that number had climbed to 80. It is still unknown which of the
five doses produced the best antiviral response as the study is
still ongoing.
Considering the wide range of dosages, the results seem quite impressive.
A nucleoside combination of this type may be particularly important
for people who cannot tolerate AZT as part of an overall combination.
In addition to optimizing the dosage, much work needs to be done
to determine how this combination will fare when used in a 3-drug
regimen including a protease inhibitor. Combinations which include
a protease inhibitor are likely to become a recommended standard
of care in the very near future.
Hydroxyurea and ddI Combination
Hydroxyurea is an inexpensive and relatively safe drug used in the
treatment of mild cancers. Research in Robert Gallo’s lab
at the National Cancer Institute showed that the drug has potential
antiviral activity by acting on factors inside the infected cell,
rather than directly on the virus itself. The effects in the lab
seemed most pronounced when the drug was used in combination with
ddI. A small study of hydroxyurea in combination with ddI shows
that the antiviral benefit of the combined drugs which has been
observed in test tubes is also now observed in humans. Twenty-six
people with 100–300 CD4+ cells, who had been on ddI for at
least 6 months, enrolled in this study. Participants received one
month of ddI alone and then received one month of hydroxyurea (either
500 or 1,000mg daily) with ddI followed by one month of ddI alone.
People receiving the higher dose of hydroxyurea had greater decreases
in viral load, with an average drop of about 1 log after four weeks
of therapy, compared to about a half log decrease for people on
the lower dose. There were no changes in CD4+ cell counts when either
dose of hydroxyurea was added, however. When hydroxyurea was discontinued,
viral load increased indicating that hydroxyurea has an antiviral
effect. Because hydroxyurea can have a slightly suppressive effect
on white blood cell production, it is not surprising that its use
did not result in CD4+ cell increases. Suppression of HIV activity
may still be useful, despite this observation, especially in instances
when other forms of treatment fail to adequately suppress viral
load.
New Drugs
A new Glaxo Wellcome drug, BW-1592, appears to be very potent. Preliminary
data from an 8 week, phase I study shows that people receiving the
drug had a greater than 2 log drop in HIV RNA levels and a CD4+
cell rise over 100. The study is ongoing with reports of even more
impressive results at higher doses. The level of antiviral activity
for this drug, even when used alone, seems equaled only by the best
protease inhibitors. It is therefore a prime candidate for combination
therapy studies which will likely start this summer. This drug also
has activity against hepatitis B in test tube studies. Side effects
noted so far include rash and fevers.
Results from a study of bis-POM PMEA (adefovir dipivoxil, from
Gilead Sciences) were recently presented. Seventy-two people with
200–500 CD4+ cells and greater than 10,000 copies of HIV RNA
received placebo, 125mg or 250mg once daily of bis-POM PMEA for
six weeks. At the end of the six week study everybody got bis-POM
PMEA for an additional six weeks. People were allowed to have been
on prior antiretroviral therapy. However, they had to stop their
antiretrovirals 2 weeks prior to their participation in this study.
People receiving either dose of bis-POM PMEA had about a 0.5 log
decrease in HIV RNA levels and about a 50 CD4+ cell increase after
12 weeks of therapy. Interestingly, people who received bis-POM
PMEA also had a decrease in their CMV DNA levels.
Summary
With the striking advances offered by protease inhibitors, proof
of the benefits of combination therapy, and the promising results
on other treatments, this period represents a renaissance for antiviral
therapy. While some critics still celebrate the failures of AZT
monotherapy in older studies like the European Concorde trial, the
field has moved dramatically forward. This class of drugs is finally
maturing, producing products with high levels of activity and modest
side effects. It fortunately comes at a time when the basic science
research in AIDS seems to be pointing to an ever more important
role for control of the virus. Perhaps for the first time in AIDS
research, it looks like patients and physicians will have the right
tools to do the job.
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