Zerit (d4T) Approved

FDA approval of d4T (brand name Zerit, chemical name
stavudine) was announced June 27; the drug should reach
pharmacies in July. Under the FDA's accelerated-approval
regulations, this drug was approved on the basis of
"surrogate markers" (improvement in blood work) plus safety
data from the large parallel-track program -- while the longer
trials needed to obtain statistical proof that the drug
increases survival or reduces opportunistic infections are
still ongoing.

The package insert for d4T -- the "labeling" approved by the
FDA, which defines the claims which can be made in marketing
the drug -- provides an accessible overview of what was known
about the drug when it was approved. A major controlled
trial, in patients with at least six months (and usually
longer) of prior AZT use, is now comparing two treatment
strategies, switching to d4T vs. continuing on AZT. Data from
359 patients in this trial has been analyzed; after 12 weeks
of treatment, those who switched to d4T had an average
increase of 22 in their T-helper count, while those who
continued on AZT had an average decrease of 22.

Meanwhile, a large parallel-track program, sponsored by
Bristol-Myers Squibb Company, the sponsor of d4T, provided
the drug free to over 10,000 people who could not use either
AZT or ddI. Those who entered this program were randomly
assigned to either a 20 mg or 40 mg dose twice daily (or a
smaller dose, depending on body weight). An interim analysis
of data from 9,226 patients showed that the survival rate was
about the same in the two dose groups.

The main side effect of d4T is peripheral neuropathy, which
was serious enough to require drug discontinuation or dose
reduction in 15 percent of the volunteers in the controlled
trial, and 21 percent in the parallel-track program. The
neuropathy may worsen temporarily after the drug is
discontinued.

Because there is no data now available on whether d4T
improves survival or reduces opportunistic infections, the
drug "is indicated for the treatment of adults with advanced
HIV infection who are intolerant of approved therapies with
proven clinical benefit or who have experienced significant
clinical or immunologic deterioration while receiving these
therapies or for whom such therapies are contraindicated." A
trial to compare d4T with AZT as initial therapy is now being
planned, but no such trial has yet been started.

The package insert (which unfortunately is usually not given
to patients with the prescription, but will be generally
available in the Physician's Desk Reference) also provides
the following information about using d4T:

* d4T can be taken without regard to meals.

* Persons with decreased kidney function excrete d4T more
slowly than normal, so their dose should be reduced; specific
recommendations are given.

* For persons with pre-existing liver dysfunction, no data is
available, so no recommendations can be made. But there are
recommendations for drug discontinuation or dose reduction if
"clinically significant elevations of hepatic transaminases"
occur during d4T treatment.

* Because of unknown risks, d4T "should be used during
pregnancy only if clearly needed," and mothers should
discontinue breast feeding if they are using the drug.