GMHC Treatment Issues 1996 Feb 1; 10(2): 8
Further human trial data on hydroxyurea and compounds with
similar effect were presented at the Third Conference on
Human Retroviruses and Opportunistic Infections. The new data
confirm the positive impression that hydroxyurea, especially,
has made in past investigations (see the September, 1995
Treatment Issues, pages 1, 2-4).
Hydroxyurea and the related drugs act by restricting the
cellular pathways by which new DNA nucleotides are made.
These gene-creating building blocks are taken up by the HIV
enzyme reverse transcriptase as HIV infects new cells. The
resulting scarcity of natural nucleotides allows nucleoside
analog drugs like ddI or AZT, which are defective
nucleosides, to play a greater role in disrupting HIV.
The most significant new piece of information on hydroxyurea
(abstract 406) was presented by Julio Montaner, M.D., head of
a Canadian pilot study of hydroxyurea among a group of
patients with CD4 counts between 100 and 350 (average CD4
count of 241) and at least six months prior ddI experience.
The objective of the study was to assess the viral load
effect of adding hydroxyurea to ddI monotherapy.
The study was set up as follows: all trial participants (26)
received ddI monotherapy for four weeks (200 mg twice a day).
The ddI alone therapy was followed by four weeks of ddI plus
hydroxyurea, with half of the group (13) assigned randomly to
a low dose (500 mg once a day) and the other half to a high
dose (500 mg twice a day) of hydroxyurea. For the last four
weeks of the twelve-week study, everyone was put back on ddI
monotherapy. Viral load (plasma levels of free HIV) and CD4
counts were measured on a daily basis.
For study purposes, an individual was defined as a
"responder" if he or she registered an HIV viral load
reduction greater than one log (90 percent). Based on this
definition the investigators found that during the four weeks
on ddI/hydroxyurea combination, nine out the 26 patients were
responders. Six out of the nine responders were on the
hydroxyurea high dose, with the remaining three on the low
dose. This difference is only great enough to statistically
suggest, but not demonstrate, that a greater viral burden
reduction can be achieved with the higher dose.
The average viral load reduction (70 percent and 90 percent
at week seven in the low and high dose arms, respectively)
was statistically significant, as was the viral load rebound
after discontinuation of hydroxyurea therapy at week eight.
This return to baseline HIV levels occurred during the first
week off hydroxyurea.
In the initial laboratory experiments at the National Cancer
Institute, inhibition of HIV-1 was still seen several weeks
after stopping drug treatment. The rapidity of the rebound in
the present human trial indicates that continued viral
suppression after withdrawal of hydroxyurea may not occur, at
least in this population with advanced HIV infection and high
CD4 turnover. (The CD4 cells arising after treatment
cessation would be unaffected by the previous exposure to
Many hydroxyurea researchers argue that the ddI/hydroxyurea
combination will be of significant benefit only for a
relatively healthy, ddI-naive population since this is where
a synergistic effect would be seen and toxic side effects
(bone marrow suppression) should be minimal.
Considering the advanced disease status and long treatment
history of the trial cohort, the viral load reductions were
impressive. Investigators are currently analyzing the
prevalence of ddI resistance in study participants' HIV and
its association, if any, with the magnitude of the response.
No serious toxicities were reported in the study, although
some conference attendees pointed out that the time on
hydroxyurea was too short to evaluate any negative effects on
blood cell counts. Likewise, no change was observed in CD4
counts probably because of the trial's brevity.
Follow-up to the French Trial
Interest in hydroxyurea had been considerably heightened by
the results of a French study involving twelve asymptomatic
HIV-positive patients (CD4 count above 250) with no previous
anti-HIV therapy. (See the September, 1995 Treatment Issues,
page 1.) The group received ddI (200 mg twice a day) and
hydroxyurea (500 mg twice a day) for three months.
In a follow-up report (abstract 291), researchers presented
data on those twelve patients, six of whom stopped the study
regimen at the end of the three-month observation period.
They also reported on an additional group of six patients
that started treatment with this combination since then and
also have completed three months of therapy.
At eight months, HIV viral load increases were reported in
five out of the six persons that stopped treatment. The other
one was stable. CD4 counts held more or less steady in four
of them. Of the six patients who have remained on therapy,
two have stable HIV levels, one had a major increase and two
had slight increases. (No data were reported for one member
of the group.) CD4 counts continued to increase in three
members of this group.
Of the six patients that started the combination recently,
two had HIV levels below detectable limits at three months,
one experienced a two log (99 percent) decrease, and the
other three a one log (90 percent) decrease. This study is
not a rigorous clinical trial and leaves a lot of room for
argument over its interpretation. Along with the Canadian
trial, it does at least provide a basis for more
sophisticated testing of hydroxyurea
Where's the Placebo?
Here in the U.S., ACTG 307, a pivotal ddI/hydroxyurea study,
was due to start last fall. According to the trial's
principal investigator, Joseph Eron, M.D., the lack of a
placebo has been a big stumbling block. Bristol-Myers Squibb,
producer of hydroxyurea (brand name: Hydrea) has yet to
provide the placebo pill, which has to resemble the real
thing. A company in Maryland is currently working on it, but
researchers are not ready yet to start recruiting. For the
latest information and current trial sites, call 800/TRIALS-
A. Other Compounds
Alternative experimental medications utilizing the same
strategy as hydroxyurea are also waiting for more extensive
Dr. W-Y Gao of the National Cancer Institute described
compounds that block the cellular enzyme known as thymidylate
synthase (abstract 5). This enzyme helps process the
nucleotides for which AZT and d4T are defective analogs. (See
Treatment Issues, September 1995, page 5. Hydroxyurea
inhibits a different enzyme, ribonucleotide reductase.) In
the test tube, very low concentrations of the anticancer
drugs FUdR (floxuridine) and 5-FU (fluorouracil) potentiated
both AZT and d4T as predicted. FUdR raised d4T's potency
eight times, and AZT's effect was six times greater in its
Dr. Gao's presentation was seconded by a report from the
Robert Johnson School of Medicine in New Jersey and the
University of Rochester (abstract 344). This group used FUdR
to potentiate AZT in the test tube.
Both FUdR and 5-FU are extremely toxic, which could limit
their use. These drugs' success as antiviral agents depends
on their effectiveness within the body at the very low,
presumably nontoxic concentrations used in the laboratory