d4T (Stavudine) Background

d4T (also called stavudine; its chemical name has been
spelled in various ways, including 2',3'-didehydro-2',3'-
dideoxythymidine) is important now for two reasons:

* A "parallel track" trial, run by d4T developer
Bristol-Myers Squibb, will soon make this drug available to
persons who have failed both AZT and ddI, and therefore have
no approved HIV treatment options; and

* Results of early trials, as well as the impressions
of researchers and others who have worked with d4T, suggest
that this drug might be somewhat better than either AZT or
ddI as a single agent. If so, d4T could be a modest but
important improvement in AIDS/HIV treatment. But the
benefits are limited, as the drug does not totally stop
disease progression. Like AZT, ddI, and ddC it can only
prevent infection of new cells, but cannot reduce viral
activity in chronically infected cells.

[Comment: d4T would be less important today if any truly
good AIDS treatment were on the near horizon. Where we are now
in HIV treatment can be illustrated by comparison with the
history of other diseases. For example, it has recently been
noted that treatment of the opportunistic infection MAC is where
treatment of tuberculosis was several decades ago -- in that one
good drug had been discovered (clarithromycin for MAC,
streptomycin for TB), although clearly other drugs would be
needed too. Today we are not yet at that stage in treating HIV,
as we only have poor to mediocre drugs: AZT, ddI, ddC, and now
(an anticipated improvement, but still in the mediocre-at-best
category) d4T.

We suspect that the most likely source of a good drug today
would be protease or tat inhibitors. But these are moving slowly
-- mainly, it seems, because of technical difficulties in the
former case, and corporate politics in the latter.]

Until better drugs are developed, the available improvements
in second-rate technology (in this case, blocking of reverse
transcriptase, which will not work for chronically infected
cells) will be important. For this reason we have prepared an
overview of d4T itself, the ongoing phase II/III trial, and the
parallel-track program which is expected to begin soon.

d4T

d4T is a close chemical relative of AZT, but it does not
have the azido group (three nitrogen atoms) in the molecule. In
test-tube studies with AZT, and in animal studies with other
retroviruses, d4T often worked less well than AZT.

But d4T may make up for this disadvantage by being processmore efficiently in human cells. Both drugs enter the cell
unchanged, but are not active against HIV until they are
chemically converted to a triphosphate form (with three phosphate
groups added to the molecule) by enzymes within some (not all)
cells. A major problem with AZT is that it tends to accumulate
in the monophosphate form (with only one phosphate group
attached, instead of three); in this form it is ineffective and
may be harmful. d4T is converted much better to the
triphosphate.

d4T has very good oral bioavailability; and unlike ddI, it
does not need a buffer to protect it from stomach acidity. Like
AZT, it partially crosses the blood-brain barrier. And HIV
strains which have become resistant to AZT are often still
susceptible to d4T -- potentially an important advantage of the
latter drug.

d4T has been given to over 250 patients in early trials (not
counting the almost 400 patients already enrolled in a large
phase II/III trial now ongoing, who have been randomized to
receive either d4T or AZT). The most important findings are:

* T-helper cell increases last longer with d4T than
with AZT, often lasting for more than a year before
returning to baseline. (The size of the increase is
probably larger, too, but we do not have exact comparisons.)

* d4T also shows antiviral activity in humans by
reducing p24 antigen.

* The main side effect is peripheral neuropathy,
similar to that caused by ddI or ddC. Some patients have
had elevated liver-function tests. These toxicities
happened most often at higher doses than are currently being
used. We have not heard of any case of pancreatitis caused
by d4T.

* The maximum tolerated dose of d4T for long-term use
is about 4.0 milligrams per kilogram of body weight per day;
above this level, toxicities are unacceptable. The dose
which will be used when the drug is approved is still not
determined, but it will probably be not far from 1.0 mg/kg,
four times lower than what can be tolerated -- probably no
less than 0.5 and no more than more than 2.0. (A much lower
dose, 0.1 mg/kg/day, has been tested and found to be too
low.)

* There is not enough data yet to know whether d4T will
work better than AZT or ddI in preventing AIDS progression
or death. (This is what the phase II/III trial should
determine.)

* d4T has not yet been tested in combination with other
antiretrovirals in clinical trials. But experts suspect
that a combination with AZT will probably not work, because
AZT would prevent d4T from being effective; using the drugs
in alternation might be OK. On the other hand, the
combination of d4T and ddI looks good in laboratory tests;
see V. Brankovan and others, "Strong synergistic anti-HIV
activity of a purine and a pyrimidine nucleoside analog, ddI
and d4T," V International Conference on AIDS, Montreal, June
4-9, 1989 [abstract # M. CP. 128]. This study found that
the 50 percent effective concentrations were 5 and 32 uM
respectively for d4T and ddI, but only 0.2 uM for the
combination; in addition, the toxicity was not synergistic
in this laboratory study. But in people, both drugs can
cause peripheral neuropathy; therefore it would be risky to
try them together, except in a carefully monitored
scientific study.

* "Underground" d4T was available recently, but then
the supply dried up, apparently because of disputes among
people involved, not because of government interference. We
heard good reports about this d4T, which was used by people
without other treatment options. However, underground d4T
is unlikely to be important in the future, because the drug
is expensive to manufacture in small quantities, and the
parallel track will soon make it available without charge to
those who need it most. And when d4T is approved it will be
available to anyone, probably for no more than the
underground drug would cost, eliminating the market for an
underground version, which no one would use if they could
get the pharmaceutical drug instead.

* d4T is quite stable, and most of it is excreted
unchanged in the urine. When cost or supply is critical, it
might be possible to recycle the drug and provide treatment
at a fraction of the price otherwise required.

Phase II/III Ongoing Clinical Trial

A large multicenter trial comparing d4T to AZT is now
recruiting throughout the United States and in Europe. Volunteers
must have T-helper counts between 50 and 500 and have received
AZT for at least six months and currently be tolerating at least
500 mg of AZT daily; they must not have used d4T, ddI, or ddC at
any time. There are also a number of other medical and
laboratory criteria for entry into this study.

This trial has now enrolled about 400 volunteers; it is
seeking a total of 700. It has 45 U. S. sites in the following
cities (list is alphabetical by state and by city within state):
Tucson, Berkeley, Los Angeles, Sacramento, San Francisco,
Torrance, Denver, Washington D. C., Ft. Lauderdale, Miami, South
Miami, Tampa, Atlanta, Chicago, Indianapolis, Kansas City,
Wichita, Boston, Baltimore, Charlotte, Durham, Omaha,
Albuquerque, Bronx, New York, Stony Brook, Philadelphia,
Pittsburgh, San Juan (Puerto Rico), Charleston, Dallas, Houston,
San Antonio, Salt Lake City, and Milwaukee.

For information about this trial, including locations and
phone numbers of sites in your area, call the AIDS Clinical
Trials Information Service, 800/TRIALS-A.