Combination Antiretroviral Treatment: New Views, Evolving Practices


The interview with Dr. Margaret Poscher, below, is the first
in a series of articles and interviews on combination anti-HIV
treatment. For over a year, it has been almost a cliche that
combination treatment is the wave of the future; however, the
actual data on how well drug combinations work in people has
been, and still remains, minimal and disappointing. But new
information has recently renewed our interest in this potential
advance:

* Laboratory studies are showing that some combinations work
much better -- or much worse -- than might have been predicted,
in suppressing HIV in laboratory cultures.

Some of these studies have been conducted over the last five
years by Marty St. Clair, Ph.D., of Burroughs-Wellcome (now Glaxo
Wellcome). Among the few drugs that she has tested so far, she
has found that certain triple combinations work best. Some of
the best results have been with AZT, plus either ddI or ddC, plus
either 3TC or nevirapine.

These laboratory studies have also suggested that it is
better to combine drugs than to alternate them. Also, it is
usually best to begin the different drugs at or close to the same
time, if possible; the combinations may be less effective if the
patient has already been using one of them for months or years,
allowing resistance to develop. And the laboratory tests suggest
that these combinations may be most active when the viral
concentration is low, suggesting that they may work better in
early stage HIV infection, than in late stage.

Conditions in the human body, of course, are very different
than in laboratory cultures. Therefore this laboratory work can
only provide guidance or suggestions as to what combinations may
be likely to work. Only human trials can tell whether or not a
particular regimen is truly promising.

Dr. St. Clair presented a preliminary report on this
laboratory work last January at the 2nd National Conference on
Human Retroviruses and Related Infections, in Washington, D. C. A
full report will be published soon.

* Recently we heard about a case of very successful use of
one of the combinations suggested by the laboratory work (AZT
plus 3TC plus ddC), by a person we know. His CD4 (T-helper)
count was 300 a year ago, then declined rapidly to 110 last
November 1, and to 70 last December 1, when he started the triple
combination treatment. In February his count was 320, and in
March it was 540. In April he had a bad case of flu, and his
count dropped to 420. Then it went up to 450, and in June 1995
was 480.

In November he had hairy leukoplakia, bad thrush, and bad
scalp lesions; he had lost weight and was sleeping up to 18 to 20
hours a day. Now all symptoms are gone, and he has gained 25
pounds and is sleeping normally. He appears to be in perfect
health.

This person, importantly, was treatment naive when he
started the triple combination. He used standard doses of the
drugs, but sometimes reduced the AZT dose from 500 mg to 400 or
300, due to stomach upset. He was using no other treatment at
the time except for acyclovir.

Certainly no single case can prove that a treatment works;
and we suspect that few people will find equally good results
from this combination. But still cases like this compel
attention, since comparable results are never seen with
conventional HIV treatment. We mentioned this experience because
it suggests a possibility, a goal, worth aiming for. Also, it
suggests designs for clinical trials; for example, if a patient
has a CD4 count below 50 and has CMV retinitis, and combination
HIV therapy raises the CD4 count to a level where CMV is not
normally a risk, will the retinitis stop progressing, thus
reducing or eliminating the need for specific CMV treatment?

* On June 30, Glaxo Wellcome applied to the FDA for
accelerated approval for 3TC, for use in combination with AZT as
first-line treatment for adults with CD4 counts under 500, and
for children who meet the CDC guidelines for treatment with
antiretrovirals. If the drug is approved for this indication, it
will probably make combination treatment the standard of care for
many (though not all) persons under 500, making it much easier to
get this treatment paid for. It will also encourage
experimentation with three-drug combinations, as approved drugs
like ddI or ddC are added to the regimen.

Today, combination antiretroviral treatment, especially
triple combinations, are more talked about than used. As we
asked around for referrals to physicians who might have
experience with triple combinations, the same names kept coming
up again and again. Most of them have only used triple
combinations with a few patients. And they have different
approaches to when and how they use these treatments; consensus
has not yet developed. This slow start for combination treatment
is not surprising, due to the lack of definitive data from
clinical trials.

The interviews in this series will examine some of the
different approaches which are in use, and why physicians make
the choices they do. Note that these interviews will focus
primarily but not only on combination treatment; they will also
look at related medical topics when they arise.