Being Alive 1998 Mar 5: 6
Fueled by numerous prior reports of efficacy, as well as a
treating community searching for new options in patients who
have failed existing regimens, hydroxyurea (brand name Hydrea)
has become a part of many anti-HIV regimens, especially over
the past year.
The amount of new information available at this Conference
seemed inappropriately small-five posters displayed at
Wednesday's session-and makes some (including this writer!)
wonder if part of the explanation might be a political one:
When a substance is already FDA-approved or otherwise easily
available, is there less pharmaceutical support for research?
(Consider interleukin-2, pentoxifylline, N-acetylcysteine,
cimetidine, and even vitamin C.) Nevertheless, several of the
studies presented do have unique features-including reports of
hydroxyurea compared with a placebo, hydroxyurea in a
protease-containing combination, and hydroxyurea's potential
salutary effects on the immune system.
Hydroxyurea has been available in the U.S. for more than 30
years, and has been FDA-approved for the treatment of certain
types of leukemia (and more recently, sickle cell disease as
well). Its purported mechanisms of action-both in leukemia and
in HIV disease-have been extensively published elsewhere and an
excellent review appeared in the March 1997 Bulletin of
Experimental Treatments for AIDS.
It was at the First National Retroviral Conference, held in
December 1993, that a team from the Research Institute for
Genetic and Human Therapy in Europe reported that hydroxyurea
inhibited HIV replication in peripheral blood mononuclear cells
and macrophages. In the presence of ddI, synergy was observed
to occur as well.
Over the ensuing years, at least four human clinical trials
were held, using hydroxyurea in addition to ddI and/or d4T.
These were generally open label trials, most of them conducted
outside of the U.S. As the results of these trials gained
publicity, showing increased viral load suppression and/or
increased CD4+ T-cell counts with little toxicity, many
clinicians began to prescribe this relatively inexpensive drug
for patients with HIV. Its cost of less than 30 cents per day
for the usually prescribed 500 mg twice-a-day dose, and the
fact that it is FDA-approved, no doubt add to its appeal.
(Hydroxyurea as well as ddI and d4T are manufactured by
Its purported efficacy lies in its ability to suppress
nucleoside triphosphate production by inhibiting the enzyme
ribonucleotide reductase. This leaves fewer
deoxyribonucleotides (DNA building blocks) available, causing
greater amounts of nucleoside analogue medications to be
incorporated into DNA. Cell replication is blocked (hence its
use in leukemia).
In addition, since the target of this drug is a human cellular
enzyme, and not an HIV-specific enzyme, there should be less
chance for resistance to occur than occurs with reverse
transcriptase or protease inhibitors. Further studies have led
to the postulation of some immune boosting effects as well.
Hydroxyurea In Open Label Combination
One Conference report was of 31 antiretroviral-experienced
patients (prior monotherapy experience: 15 AZT, 7 ddI) with
mean viral load of 105,700 copies/mL and mean CD4+ T-cell count
of 231 cells/mm<. They all received a single daily dosage of
1000 mg of hydroxyurea in addition to ddI and d4T. For the 14
patients evaluable at 12 weeks, the mean decline in viral load
was 1.3 log; during this time the CD4+ T-cell count increased
by approximately 80 cells/mm< for 12 patients at 16 weeks of
therapy. Two of the patients developed neutropenia (low white
blood cell count) which was reversible upon cessation of the
drug. This study had neither placebo nor control group, and
thus it is difficult to interpret the results as definitively
favoring the use of hydroxyurea. A decline of 1.3 log is not
uncommon with two nucleoside analogues.
Finally, A Placebo-Controlled Trial!
An abstract from the Swiss HIV Cohort Study looked at comparing
hydroxyurea 500 mg twice per day vs. placebo in 144 subjects,
all of whom also received ddI 200 mg plus d4T 40 mg twice a
day. Three-quarters of the group was antiretroviral-na�ve, and
the mean viral load at study onset was approximately 30,000
The viral load suppression at 12 weeks was significantly
greater in the group which received hydroxyurea-2.3 log, versus
1.7 log in the placebo group.This study is important in that it
demonstrates the added efficacy of hydroxyurea in a
placebo-controlled trial. It also had a significant number of
subjects, allowing for better statistical interpretation of the
Yes, and What About the Immune System? Another poster, which
was presented by Dr. Galpin of the Shared Medical Research
Group, focused on the immune response to hydroxyurea. Since HIV
infection is characterized by a progressive loss of naive,
programmed (memory), and long-term memory cells, the authors
asked if effective viral suppression could reverse these trends
An interim analysis at week 20 showed a statistically
significant increase of naive and long-term memory lymphocytes.
Finally (Again), Hydroxyurea With a Protease Inhibitor! In what
might be the first controlled study involving hydroxyurea with
a reverse transcriptase inhibitor and a protease inhibitor, Dr.
Frano Lori described eight patients with relatively recent HIV
infection (mean duration 13 months) who were placed on
hydroxyurea 300 or 400 mg thrice daily plus ddI 200 mg twice a
day and indinavir 800 mg three times a day. These were compared
to a control group of eight patients with comparable HIV
infection who were not treated. After an average treatment
period of five months, all members in the treated group
achieved undetectable viral loads (average starting value had
been 494,000 copies/mL) and a statistically significant rise in
CD4+ T-cell count of 116 cells/mm< (starting value 448
cells/mm<). Also, immune system parameters which were measured
all showed significant improvement in the treated group as
compared to the control.
Further study will help define how much immune reconstitution
might occur with the use of hydroxyurea therapy.
Where We're At Today
The various studies presented at the Conference added to the
pool of data indicatingthat hydroxyurea may play some role in
HIV treatment, but that role has yet to be validated in a large
double-blind placebo-controlled randomized human clinical
trial. It is likely this will never happen, since hydroxyurea
is already an FDA-approved drug. But the tireless advocacy of
persons with HIV as well as their providers, in this era when
failure of existing regimens and the threat of widespread
resistance looms wider than ever, indicates that such a study
could shed invaluable light on the role hydroxyurea can play in
Among the many questions which remain:
How truly effective is hydroxyurea's antiviral and immune
boosting activity? What is the most appropriate dosage?
Since it has a half-life of 2.5 hours, should a
four-times-daily dosing be considered/tested?
What is the risk of long-term side effects in using an
antimetabolite such as hydroxyurea which suppresses cellular
replication (drugs which have been used to treat leukemia and
cancers have sometimes caused variations thereof)-especially in
someone who is already immunosuppressed?
If it is to be used in HIV treatment, what is the best timing
of administration? Should hydroxyurea be used as initial
therapy with nucleoside analogues, perhaps to "spare" protease
use until later? As an adjunct to a regimen once most or all
approved anti-HIV regimens have failed? (This is where most of
its use in the U.S. has occurred to date.) As part of a
What is/are the best drug(s) with which to prescribe
hydroxyurea? (There is a paucity of data on its combination
with 3TC, NNRTIs, or any protease inhibitor other than
Does hydroxyurea's claimed penetration of the blood-brain
barrier afford additional advantage in reducing viral burden in
Are there other antimetabolites which might have comparable (or
better) efficacy in treating HIV disease?
These are the issues and questions we must examine fully before
we can determine hydroxyurea's role as a weapon against HIV.
This article is reprinted (and slightly condensed) with
permission from Healthcare Communications Group, LLC. This
article is from a program made possible thanks to unrestricted
educational grants provided by Agouron, Amgen, Roche
Laboratories and Roxane Laboratories. Full summaries from the
Fifth Retrovirus Conference are available at