DDC Approved for AZT Combination

Late Friday, June 19, the U. S. Food and Drug Administration
approved ddC (brand name HIVID) for marketing to certain
patients for combination use with AZT. The approval was
announced the following Monday. Developer Hoffmann-La Roche
distributed supplies of the drug very rapidly, following
plans for quick distribution developed since late 1991.
According to the company, ddC was distributed to wholesalers
in 12 areas with large numbers of AIDS patients by the day
approval was announced, and nationwide the following day.

Patients now receiving free drug through the expanded-access
program for combination therapy can continue to receive
supplies for two months, to give them time to make
arrangements with insurance companies or other third-party
payers. The ongoing expanded-access program for ddC
monotherapy, for patients with AZT intolerance or failure,
will continue, but will not add any new patients.

Hoffmann-La Roche has started a program, called ASSIST(, for
physicians and other health care providers to obtain
reimbursement information to help patients pay for ddC plus
AZT combination therapy. Health care providers can call the
ASSIST Hotline, 800/285-4484, 9 a.m. to 8 p. m. Eastern time
Monday through Friday, for information about insurance
companies and HMOs in all states, and about Federal
reimbursement programs. The company also has the Roche
Indigent Patient Program, started in 1963, which, according
to the company, "provides all Roche prescription drugs to
patients who have been identified by their physician as
unable to pay for treatment." According to a Roche
spokesperson quoted in a June 22 press release, "No one in
need of a Roche medication will go without it because of
their inability to pay."

DDC was approved in Austria on April 7, 1992. Roche has also
applied for marketing approval to the 12 European Community
members, and to 11 other European countries.

Approved Indications for ddC

The official "labeling" for ddC, approved by the FDA,
emphasizes caution since less is known about this drug (the
first drug officially marketed under the FDA's new
"accelerated approval" policy) than about most drugs when
they are approved. While the drug's safety and toxicity are
fairly well known, due to the expanded-access programs which
have enrolled over 10,000 patients, there is no definitive
proof that the drug is beneficial to patients. Instead, there
are two small studies, both of which showed substantially
greater T-helper count improvements with the drug combination
than would be expected from AZT alone. The following is the
first paragraph of the "indications and usage" section of the
labeling for ddC:

"Combination Therapy with Zidovudine in Advanced HIV
Infection: HIVID (zalcitabine) in combination with zidovudine
is indicated for the treatment of adult patients with
advanced HIV infection (CD4 cell count <= 300 cells/mm3) who
have demonstrated significant clinical or immunologic
deterioration. This indication is based on limited data from
two small studies in which zidovudine-naive patients with a
CD4 cell count <= 300 cells/mm3 who were treated with HIVID
plus zidovudine had a greater CD4 response than patients
treated with zidovudine alone (see "Description of Studies").
Neither study included a concurrent control group taking the
currently recommended zidovudine dose of 100 mg q4h, and
these studies were not designed to measure the clinical
efficacy of the combination. No data are currently available
on the combined use of HIVID and zidovudine in patients who
have previously received zidovudine monotherapy, although
controlled studies are ongoing. At present there are no data
available from controlled or uncontrolled studies addressing
whether an effect on CD4 cell count would be observed by the
addition of HIVID to patients who are currently receiving
zidovudine or who had previously been exposed to
antiretroviral therapy. Because zidovudine has been shown to
prolong survival and decrease the incidence of opportunistic
infections in patients with advanced HIV disease, zidovudine
monotherapy should be considered as initial therapy for adult
patients with HIV infection who have evidence of impaired
immunity (CD4 cell counts of <=500 cells/mm3)."

[Note on terminology: Drugs sometimes have three names
because a generic drug name different from the familiar
chemical name is used; there is also at least one proprietary
brand name. Thus ddC (chemical name) is zalcitabine (generic
drug name) and HIVID (brand name); until exclusive rights to
the drug expire, however, there will only be one brand.
Similarly AZT has the generic name zidovudine, and the brand
name Retrovir. For any drug, AIDS TREATMENT NEWS prefers the
name which is most familiar to our readers.]

*** Three-Drug Study Begins: AZT Plus DDC Plus Alpha
Interferon, Eight U. S. Cities

by John S. James

Burroughs Wellcome Co is now beginning a major study of a
three-drug combination -- AZT plus ddC plus alpha interferon --
in eight U. S. cities: Houston, Manhasset (New York),
Nashville, Salt Lake City, San Francisco, Tampa, Washington,
and Wichita. It will compare this three-drug treatment with
the two-drug combination AZT plus ddC (which was recently
approved by the FDA). The goal of this 76-week study is to
see if either regimen can restore T-helper counts to normal
(over 800) for at least six months, in volunteers with
starting T-helper counts between 300 and 500 -- and to see if
the three-drug combination works better than the two-drug
one. The standard doses of AZT and ddC will be used; the
alpha interferon dose will be fairly low, 3MU per day.
Everyone in the study will get at least AZT and ddC, and
there will be no placebo. A total of 250 volunteers will be
enrolled, with 125 assigned randomly to each of the two
treatment regimens.

This study is important because laboratory tests have shown
that the three-drug combination works particularly well
against both laboratory strains of HIV, and "wild" strains
taken from patients. The graph below (page 3) shows some of
these laboratory results. The combination of AZT and ddC
worked substantially better than AZT alone, and better than
the other two-drug combinations tried (AZT plus alpha
interferon, and AZT plus foscarnet; foscarnet, while best
known for its anti-CMV use, also has some anti-HIV activity).
But the three-drug combination of AZT, ddC, and alpha
interferon worked far better than any other regimen tested.
What is being measured in all these cases is cytopathic
effect, meaning the damage to cells in the laboratory when
they are infected by HIV and then treated with antivirals.

The alpha interferon used is Burroughs Wellcome's Wellferon,
which is different from most of the alpha interferon approved
in the United States. Wellferon, approved in some European
countries for treating hepatitis B but not approved in the
U. S., is a "natural" alpha interferon, produced by
transformed human cells; it contains at least 16 varieties of
human alpha interferon. Many brands of alpha interferon, by
contrast, are made by genetically engineered non-human cells;
they contain only a single variety of the interferon. No one
knows if this difference matters when alpha interferon is
used as an HIV treatment. But Wellferon was used in the
laboratory tests of the three-drug combination, and it will
be used in the trial. (Recombinant alpha interferon has,
however, often been used in AIDS treatment.)

This study is only open to volunteers with T-helper counts
between 300 and 500, who do not have AIDS, and who have had
no more than three months of any antiretroviral treatment
(such as AZT, ddI, or ddC). The reason for these eligibility
criteria is that the drugs may work best if the virus has not
already developed resistance to them. This is why patients
must not have received AZT, etc. before -- or received only a
little of it.

The reason for requiring that volunteers have a relatively
early stage of disease is that alpha interferon is normally
present in the body -- and when AIDS develops, this level often
becomes abnormally high. Therefore the patient's virus may
already have become partly resistant to alpha interferon,
which could cause the drug would work less well in the trial.
The selection criteria were designed to find patients who are
unlikely to be resistant to any of the three study drugs when
they begin the combination treatment.

This does not mean that the combination would not work at
later stages of HIV disease, in some patients at least. But
for purposes of this trial, the entry criteria were designed
to give the treatment the best possible chance to show a
successful result. And since AZT, ddC, and alpha interferon
are all approved, any U. S. physician can prescribe them;
patients who are not in the trial could try the same three-
drug combination now, no matter what their T-helper count.

The reason for the entry requirement of a T-helper count no
greater than 500 is, presumably, because no antiretroviral
treatment is officially recommended at this time for persons
with counts greater than 500. Also, it would be hard to know
what improvement to look for if T-helper counts started in or
near the normal range -- especially since there has been little
experience so far with anti-HIV drugs in this patient group.

Comment

This study is well designed. It asks an important question,
it could answer that question, and the answer could improve
medical practice. And there is an excellent scientific
rationale, based on (1) especially good results in laboratory
tests for this three-drug combination, (2) the fact that
three or more drugs in combination have been needed
historically for successful treatment of difficult diseases
like tuberculosis and cancer, and (3) the fact that HIV can
develop drug resistance very rapidly -- which further increases
the rationale for combination therapy, since it is unlikely
that an organism will develop three or more different kinds
of drug resistance simultaneously.

One question which has often been asked is why the two-drug
combination AZT plus ddC works as well as it seems to, in the
two small studies which have provided all the results we have
so far on this regimen. Those studies were in persons with
fairly advanced disease; in the most important trial, called
ACTG 106, the median T-helper count before patients began the
treatment was about 70. One possibility -- just a speculation
at this time -- is that the treatment worked as well as it did
because the two-drug combination was really a three-drug
combination, since the level of alpha interferon in the
patients already at that stage of the disease would be likely
to be high. If this is true, then the two-drug combination
might not work as well in early disease -- unless interferon
were added to the regimen.

All this is guesswork, however, until the three-way
combination trial is done. Theories and laboratory tests
cannot prove that a treatment works in people. The only way
to know with confidence is to run a well-designed trial.

This trial is important because, while waiting for better
drugs to treat AIDS or HIV, we need to learn how to make the
best use of the drugs already available. This three-way
combination study is at the leading edge of that effort.

For More Information

Potential volunteers for this trial should call the study
coordinator at a site convenient for them. Volunteers must be
at least 13 years old, have T-helper counts between 300 and
500, and not have AIDS; they must not have used AZT or other
antiretrovirals for more than three months. There are several
other exclusion criteria, mostly for medical conditions (such
as anemia) which could increase the risk of using one of the
drugs. Note that over 20 visits, for blood work, etc., are
required during the course of the 76-week study. The alpha
interferon is given once per day by subcutaneous injection,
which can be done by the patients themselves at home.

As this article went to press, we learned that institutional
review boards have approved the trial at all the study sites
(listed below), and that the first two patients have been
enrolled and are now receiving the drugs.

The study coordinators for the Burroughs Wellcome three-drug
combination trial can be reached at:

Houston: Baylor College of Medicine, 713/798-4720.

Manhasset, New York: North Shore University Hospital,
Division of Infectious Diseases, 516/562-1527.

Nashville: Vanderbilt University School of Medicine, 615/343-
6693.

Salt Lake City: University of Utah School of Medicine,
801/581-4878.

San Francisco: ViRx, Inc., 415/474-4440.

Tampa: University of South Florida, Div. of Infectious
Diseases, 813/974-3163.

Washington: Georgetown University Medical Center, 202/687-
5378.

Wichita: University of Kansas School of Medicine, 316/261-
2655.