Valacyclovir Study Stopped -- Worse Survival


In an unexpected setback for Burroughs-Wellcome -- but one
which might turn into good news for people with AIDS -- a
study of valacyclovir was stopped early because patients
assigned to that drug had worse survival than those in either
the low dose or high dose acyclovir arms, which were intended
as control groups for the valacyclovir treatment.

Valacyclovir is a prodrug of acyclovir -- meaning a drug
which turns into acyclovir inside the body. Its advantage is
that higher doses can be absorbed orally than when acyclovir
itself is given. Therefore, doses which would otherwise
require intravenous acyclovir can be given orally with
valacyclovir. Burroughs-Wellcome has focused recent
development work on valacyclovir rather than acyclovir,
because the patent on acyclovir will soon run out, and that
drug will become generic -- meaning that it will be
inexpensive for the purchaser, but not very profitable for
the company.

The study which was stopped, called ACTG 204, had been run by
the AIDS Clinical Trials Group (ACTG) with support from
Burroughs-Wellcome. The purpose was to see whether
valacyclovir could help to prevent CMV disease in persons
with advanced HIV infection (CD4 count under 100).

Due to ethical problems with using a placebo in such a study,
low dose and high dose acyclovir regimens were used for
control (comparison) groups. High-dose acyclovir has been
shown to prevent CMV disease in organ-transplant patients
(who have immune deficiencies due to immune-suppressive drugs
taken to prevent rejection of the new organ); but prior
attempts to use it to prevent CMV disease in AIDS have not
been promising. The theory behind ACTG 204 was that the
higher dose possible with valacyclovir might provide a
practical treatment to prevent CMV disease.

But this study was stopped on February 13 because there were
more deaths in the valacyclovir arm than in either acyclovir
arm. No one knows why this happened. But we have learned that
volunteers assigned to the valacyclovir arm were on the drug
for less time than those assigned to the acyclovir arms. And
the main cause of death -- progression of HIV disease --
seemed to be similar in all the arms.

Comment

This study may stimulate research in use of acyclovir to
increase survival by persons with late-stage AIDS. Since
those assigned to acyclovir lived longer than those assigned
to valacyclovir, either the acyclovir was helping, or the
valacyclovir was hastening death, which seems unlikely.

One possibility is that the valacyclovir dose was too high
for this patient population, leading to side effects and
interruption of treatment, resulting in more time off drug in
the valacyclovir arm. The acyclovir arms may then have shown
a greater survival effect because of greater time on
treatment, or greater consistency of treatment. A recent
epidemiological study using the MACS (Multicenter AIDS Cohort
Study) database suggested that "consistent use of acyclovir
at a dose sufficient to suppress herpetic recurrences (that
is, 600 to 800 mg/day) has a clinically significant effect on
prolonging survival in a well-characterized cohort with
extensive previous exposure to herpesvirus infections" (D.S.
Stein and others, "The Effect of the Interaction of Acyclovir
with Zidovudine on Progression to AIDS and Survival," ANNALS
OF INTERNAL MEDICINE, July 15, 1994, pages 100-108) --finding
that consistent use, not high dose, seemed to matter. The
same study also found the effect in late-stage disease --
another finding consistent with ACTG 204.

There have also been negative results. For example, two
studies presented at the recent Human Retroviruses conference
in Washington, D.C., failed to find a survival benefit of
acyclovir. But it also appears that neither of them can rule
out a benefit, due to certain limitations of those studies.

We hope to learn more about what happened in ACTG 204 at the
semi-annual ACTG meeting next week. We especially want to
know how the two acyclovir arms compared, and any details in
the differences in outcome among the valacyclovir, high-dose
acyclovir, and low-dose acyclovir arms. And we want to see
how researchers and physicians interpret this very unexpected
result.

ACTG 204 might accidentally have been the controlled study
needed to focus research interest in acyclovir and survival
-- with the valacyclovir arm unintentionally providing the
control. This interpretation will be supported or
contradicted as more information becomes available.