ddC Background

ddC has become part of a de facto standard of care for
thousands of people, before being officially approved for any
human use. How did this situation come about?

ddC (2',3'-dideoxycytidine), an experimental antiretroviral,
is a nucleoside analog (in the same class of drug as AZT). ddC,
which has been available from chemical supply houses for years
(it is used in DNA experiments in laboratories) was one of the
first drugs tried as an anti-HIV treatment. But nobody knew that
the appropriate dose was very small -- a hundred times or more
less than the dose of AZT or ddI. Therefore the first trials used
doses which were far too large, which caused serious, crippling
neuropathy. As a result, researchers largely lost interest in
the drug for about two years. When it was learned that lower
doses might be tolerable and effective, interest revived; there
have now been over 20 human trials of ddC that are either
finished or ongoing.

The most scientifically definitive trial of ddC as a single-
drug treatment for patients without prior AZT therapy recently
ended in failure. The trial, known as ACTG 114, tested ddC alone
vs. AZT alone in patients with AIDS or advanced ARC. This
national study, with more than 600 volunteers, was stopped a year
earlier than planned, by the study's Data Safety Monitoring
Board, or DSMB (which periodically meets and secretly "unblinds"
the trial, to see if the results are so extreme that it would be
unethical to continue). The DSMB found that there were 59 deaths
in the 320 patients assigned to ddC, compared to 33 deaths in the
315 assigned to AZT -- meaning that AZT clearly worked better
when used as a single drug, at least at the doses being tested.
(ddC might still be used for patients who cannot tolerate or no
longer respond to AZT and have no other choice; trials to test
this use are continuing.)

Even before this result came out, almost all of the interest
in buyers' club ddC concerned its use in combination with AZT,
not its use as a single drug.

ddC and AZT In Combination

A small clinical trial of HIV treatment with a combination
of AZT and ddC was finished in November 1990, but not formally
published for over a year (TC Meng and others, Combination
Therapy with Zidovudine and Dideoxycytidine in Patients with
Advanced Human Immunodeficiency Virus Infection: A Phase I/II
Study, Annals of Internal Medicine, January 1, 1992, pages 13-20;
also see accompanying editorial by Anthony S. Fauci, M. D., pages
85-86). Project Inform and AIDS TREATMENT NEWS published the
major results of this study in November 1990 (see "ddC/AZT
Combination: Promising Early Results," AIDS TREATMENT NEWS #115,
November 23, 1990). In June 1991 the results were presented at
satellite seminars at the VII International Conference on AIDS in
Florence.

In any event, long before the scientific paper was
published, the results of this study had established a de facto
standard of care among many of the best-informed patients and
physicians -- a standard which includes a drug not officially
approved for any medical use. While exact figures are not
available, low estimates are that several thousand patients --
most at the suggestion of their physicians -- are obtaining ddC
at buyers' clubs to use in combination with AZT, which they
obtain by prescription. But this major growth of combination
anti-HIV therapy also took place largely outside of public view,
as AIDS activists (including this newsletter) were concerned that
too much attention could pressure the FDA to crack down, cutting
off a lifeline on which thousands depended. Now the attention
has come anyway -- even before the recent quality-control issue.

Behind the delay in releasing the scientific results was an
intense but quiet controversy in the AIDS research community. Our
best understanding of this controversy (and we cannot claim
objectivity) is that the study in question, officially called
ACTG 106, with principal investigators Margaret Fischl, M. D.,
and Douglas Richman, M. D., was designed as a small trial (with
56 patients total) to test the safety of using various doses of
ddC and AZT in combination.

To everyone's surprise, not only did the combination seem
safe, it also appeared to work much better than any other anti-
HIV treatment known. All volunteers had AIDS or advanced ARC,
with average T-cells counts under 100 at the start of treatment,
but these averages went up with peak increases of at least 70 to
120 above the starting count, depending on dosage group. These
T-cell rises lasted about twice as long as would have been
expected with either drug alone, and over two thirds of the
patients on the four appropriate combination doses had T-helper
rises of at least 50 on two consecutive monthly measurements.
Very few opportunistic infections occurred after the first five
weeks of the study; several occurred in the first five weeks,
presumably before the treatment had time to be fully effective.

Before this study, the "conventional wisdom" had been that
persons with T-cell counts below 100 would not recover even if
the AIDS virus could be entirely stopped, because the immune
system had been too badly damaged. This small trial showed how
much could be done with improved antiviral treatments alone, even
without any immune-based treatment to help repair damage which
had already occurred.

But this study was not designed or intended to test the
efficacy of the combination treatment -- only to test its safety.
The number of patients was small. The study was unblinded, and
patients were not fully randomized in their assignment to
treatment groups. New patients were added to the treatment
groups to replace those who left, for various reasons, in the
first eight weeks. The treatment groups were not always well
balanced, with one dosage group having a median T-helper count as
high as 103 at baseline, another a median as low as 35. (But the
group which did best also started with a low median T-helper
count, of 47.) And no patients received standard treatment for
comparison; one group received AZT alone, but only 150 mg per day
-- a dose which this study showed is too low.

These issues would not make much difference for a
preliminary safety trial, but they would have been avoided in a
study designed to collect definitive efficacy information. ACTG
106 was intended as a preliminary study; if results were good, it
would be followed by a much larger efficacy trial. (That larger
study, called ACTG 155, is now under way. It includes over 1,000
volunteers randomly assigned to one of three groups: AZT alone,
ddC alone, or the combination).

What happened with ACTG 106 is that scientists and people
with HIV drew different practical conclusions from it. Scientists
who run clinical trials are interested in maintaining scientific
standards, in doing studies correctly so that they get solid,
trustworthy results. People with life-threatening illnesses, on
the other hand, are interested in using whatever knowledge is
available to make the best treatment decisions they can.

What has been most persuasive to us about ACTG 106 is that
it is hard to interpret the outcome other than as showing that
the combination treatment of ddC with AZT works much better than
any conventional treatment. Because of the small number of
patients, it could be argued that the benefits seen might
conceivably have been due to chance. But both the size and the
consistency of the results makes this possibility unlikely.

Why doesn't the FDA just approve ddC? (Over a year ago, a
formal petition to the FDA by organizations representing almost
all HIV physicians in San Francisco urged that the available data
for ddC (and ddI, since approved) both be evaluated for possible
approval; see "ddC/ddI Approval Update," AIDS TREATMENT NEWS,
January 4, 1991.) The reason for reluctance is that the FDA
would have to base approval largely on ACTG 106 -- but the Agency
wants much more data than that before approving a drug. The FDA
usually demands more than one study, larger studies, and studies
designed in advance to test drug efficacy.

Expanded Access to ddC

It would be possible to have a regulatory system designed to
approve drugs as soon as there was a rational case for physicians
and patients to use them. Unfortunately, that is not the system
we have. Often there is a compelling medical case for a drug
long before the data available meets FDA standards for approval.
To relieve the resulting harshness, a long series of early-access
ideas (with names like "compassionate use," "treatment IND,"
"parallel track," and currently "expanded access") have been
tried. All these programs have been seriously limited by the
reluctance of pharmaceutical companies to pay for them. Ideas
for more basic reforms have been tied up in partisan politics,
with Democrats and Republicans each apparently willing and able
to block plans acceptable to the other.

But expanded access is the option (other than the buyers'
clubs) which is available now to provide ddC for combination
therapy pending marketing approval by the FDA, for patients who
cannot enter a clinical trial. Negotiations are underway at this
time to liberalize the Hoffmann-La Roche program which is already
supplying ddC to over 8,000 patients, to allow those receiving
ddC in this program to combine it with AZT.

Even if combination treatment is allowed, there is still the
issue of who will qualify. The data on combination use is for
patients with T-helper counts under 200. But many patients with
higher T-helper counts have been using the combination (with
buyers' club ddC), since it is likely, although not yet proven,
that the combination will be a more effective and lasting
antiviral than AZT alone at any stage of infection.

Some patients with T-helper counts between 200 and 500 will
be able to obtain treatment by volunteering for ACTG 175, a major
new study which will compare four different treatment regimens:
AZT alone, ddI alone, combination treatment with ddI plus AZT,
and combination treatment with ddC plus AZT. ACTG 175 is now or
soon will be recruiting in the following cities: Boston;
Buffalo; Chicago; Los Angeles; Miami; New York City; Rochester;
San Diego; San Francisco; Seattle; St. Louis; Stanford; Syracuse;
and Torrance, CA; there might also be a site in Hawaii. For more
information about this trial, call the AIDS Clinical Trials
Information Service, 800/TRIALS-A.

Note: As we went to press, Hoffmann-La Roche announced that
two new expanded-access programs would provide ddC for
combination use:

"In order to make HIVID [ddC] available in the most
efficient way possible, a simplified open-label program will
be implemented within the next two weeks. Rapid enrollment
will be enhanced through the use of streamlined entry
criteria and limited data collection. Symptomatic HIV
infected individuals with CD4 counts [T-helper cell counts]
of 300 or less or asymptomatic individuals with CD4 cell
counts of 200 or less who cannot participate in controlled
clinical trials will be eligible to receive HIVID for
combination use.... Physicians should call the ddC
Coordinating Center at 800/ddC-21-HIV (800/332-2144) between
9 a.m. and 8 p.m. (EST) for enrollment information. Like
all Roche investigational drug programs, HIVID will be
provided free of charge.

"In the second program, to be designed with input from the
AIDS community and the government, Roche will provide HIVID
for combination therapy in healthier HIV infected
individuals -- those with CD4 cell counts up to 500. This
will be the first time that a so-called Large Simple Trial
will be implemented in the study of an experimental AIDS
drug. Roche will work with several community research
consortia to initiate a trial that could potentially involve
thousands of patients."