1993 Nucleoside-Analog Trial Results Expected

The past year has seen significant developments in the area of basic
nucleoside analog antiretrovirals -- AZT, ddC, ddI, and d4T. DDC was
finally approved, for combination use; ddI's approved indication was
expanded, and promising data on combination use with AZT was revealed;
d4T began a parallel- track program; and a European-Australian study
supported the use of AZT by people with T-helper counts up to 750. The
coming year will bring further developments for these drugs and
combinations of them, as well as for 3TC, another nucleoside analog,
and a three-drug combination of AZT, ddC, and alpha interferon.
It is rarely possible to say exactly when data from specific trials
will be made public; the timelines mentioned below can only be
approximate.

The first key development in 1993 will be the long-awaited release of
data from ACTG 116A, a study comparing AZT to ddI in people with fewer
than four months' prior AZT use. This amounts to comparing the two
drugs as first-line therapy -- and suggesting which drug patients
starting anti-HIV therapy should use. By mid-January, it should be
known whether ddI in this circumstance is more effective, less
effective, or about the same as AZT. The study group had T-helper
counts under 300, but the results might well apply to people starting
treatment at all T-helper levels.

AZT has so far been the standard first-line therapy; should this study
prove it to be less effective than ddI, there would be a major
reassessment of how these drugs are used, affecting not only clinical
practice but probably some ongoing trials as well. If the two drugs
show equivalent efficacy, or if AZT is more effective than ddI, the
current standard of care may not be much altered.

Also long-awaited are the results of ACTG 019, a large and very
long-running trial that compared AZT to placebo in people who started
with a wide range of T-helper counts -- about half of them over 500.
Data on the group who started with counts over 500 should provide the
clearest answer from any U.S. study on the value of AZT (and, by
implication, other nucleosides) in people in early stages of infection.
If AZT delays disease progression in this group, there could for the
first time be an FDA-approved therapy for people with T- helper counts
over 500. Data from ACTG 019 may be available as early as February, or
if not, by mid-year.

The comparable and equally long-running Concorde study in Europe also
looks at AZT versus placebo in people starting with a wide range of
T-helper counts. Data from the Concorde study also may be available
early in the year, or by mid- year.

By late spring, final data is expected from ACTG 155, a study which
compared AZT to a combination of AZT and ddC in people with fewer than
200 T-helper cells. The FDA, on the basis of two smaller studies,
approved ddC for combination use with AZT, but the data from ACTG 155
will be critical in confirming the value of combination therapy. If
the results show an advantage for the combination, the current label
indications for AZT/ddC use (which are widely considered to be somewhat
tentative and confusing) may be clarified and strengthened by the FDA.
At the 1992 International AIDS Conference, three small studies reported
interim data on combinations of AZT and ddI. All three have been
completed or are near completion, and are likely to publish final data
in the first half of the year. These studies used different doses and
entry criteria and monotherapy control groups, making it difficult to
compare results; however, should final data indicate an across-the-
board advantage for combining AZT and ddI, there would then be at least
as much data on the AZT/ddI combination as there was on the AZT/ddC
combination when the FDA approved ddC. A change in clinical practice
and in FDA indications might result.

(It should be noted that ACTG 175, the large trial comparing
combinations of AZT/ddI and AZT/ddC to AZT and ddI as single agents, is
not expected to make public any results in 1993.)
The ongoing d4T trials are not expected to announce any results this
year. At least one pilot study combining d4T with ddI is planned;
others may follow.

Only one nucleoside in early trials appears to be moving smoothly
toward wider use. 3TC is now in late dose-ranging studies, and is
expected to start large Phase II comparative studies in the spring
(similar in some ways to the d4T trials now in progress). Sources have
told us that this drug has so far shown clear anti-HIV activity and no
serious side effects. It could be speculated that, when these Phase II
trials start, there might also be a role for a 3TC expanded- access
program, but it is too soon to know.

Finally, two studies comparing the combination of AZT and ddC to a
three-drug combination of AZT, ddC, and alpha interferon will be
continuing through the year. Late in the year, some interim data might
be available from the larger of these studies, looking at people with
T-helper counts between 300 and 500. Obviously, there are a number of
possibilities for studies of various three-drug combinations, and
results from this trial could stimulate that research.

Comment

Nucleoside analogs are often discounted by people who argue,
incontestably, that there are stringent limits to what these drugs can
do and that their various side effects often cause great problems to
patients. Nucleosides have always been regarded as a stopgap until
better treatments arrive.

That may be true, but there is a fairly clear understanding of how they
work and how their side effects can sometimes be managed; three are
FDA-approved and two more may be on the way to approval; and they are
backed by big drug companies with the resources to develop them
quickly. Although nucleosides are of limited efficacy, those limits may
not turn out to be so stringent as was once thought, if up to five
drugs come to be used serially and in combinations. Therefore, any new
availability of nucleosides or new information on how to use them is
important.