AIDS Treatment Update, Issue 64, April 1998
Hydroxyurea is a cheap, licensed drug used in the treatment of
some forms of leukaemia. A few years ago, researchers found
that it can also boost the antiviral effects of ddI in
test-tube studies (see AIDS Treatment Update issue 26). The
Fifth Conference on Retroviruses and Opportunistic Infections
held in Chicago in February heard the results of several
treatment studies looking at its risks and benefits.
Swiss researchers tested hydroxyurea in a placebo-controlled
trial, comparing a group of 72 people taking
d4T/ddI/hydroxyurea with a control group of 72 people taking
just d4T/ddI. Their average viral load at baseline was about
30,000. After 12 weeks, 54% of people receiving hydroxyurea had
achieved viral load below 200, compared with only 28% of those
not receiving hydroxyurea. The proportions achieving viral load
below 20, measured with an ultra-sensitive viral load test,
were 19% and 8% respectively (abstract 656).
In another study, 31 people with higher viral load (average
100,000) were treated with d4T/ddI/hydroxyurea. There was an
average 1.3 log reduction in viral load and about 50 CD4 cell
increase after 12 weeks of therapy, and after 16 weeks eight
out of eleven participants had achieved viral load below 500
A number of cases have also been reported in which hydroxyurea
treatment appears to be associated with disappearance of
detectable HIV, even in latently infected cells containing HIV
proviral DNA (the most stubbornly persistent form of HIV's
genetic material). Dr Franco Lori presented data on 24 patients
treated with ddI/indinavir/hydroxyurea, of whom 10 started
treatment just weeks after infection. After 11 months, the
average CD4 count increase was 168 and all participants had
viral load below 500. Seven out of eight people who underwent
lymph node biopsy had no detectable viral RNA in their lymph
nodes, while two out of six had no detectable proviral DNA
either (abstract LB11).
One patient in the study was investigated even more closely.
Even after increasing the sensitivity of the tests for proviral
DNA and HIV RNA up to 60-fold, it was only possible to detect
one cell in ten million that was able to produce infectious HIV
particles. This result is even more dramatic than those
achieved after 2.5 years of triple therapy in David Ho's
laboratory. This individual has now been off treatment for 13
months without any viral load rebound. However, it has been
suggested that these impressive findings may be a consequence
of the very early stage at which treatment was started, rather
than of the specific drugs used.
These intriguing results are still very preliminary, and need
to be confirmed in much larger studies with proper control
groups for comparison.
Some doctors are also using hydroxyurea as part of salvage
therapy regimens for people who have developed resistance to
many or all of the licensed anti-HIV drugs. One test-tube study
found that even ddI-resistant strains of HIV remained
susceptible to ddI when it was given in combination with
hydroxyurea. Since hydroxyurea works by affecting the human
cell rather than HIV (see box opposite), HIV resistance
mutations are unlikely to have any effect on hydroxyurea's
Most studies testing hydroxyurea are using it in combination
with ddI, since this combination seemed to be the most
effective in the test-tube. A report at the Retroviruses
conference two years suggested that hydroxyurea did not boost
the anti-HIV effects of AZT in laboratory tests. Other
test-tube studies suggest that the only anti-HIV drugs whose
effects are likely to be enhanced by hydroxyurea are ddI,
abacavir (1592U89) and adefovir dipivoxil.
A much lower dose of hydroxyurea (often 500mg twice daily) is
used when treating people with HIV, compared with the dose used
for treating leukaemia. Nevertheless, the downside of
hydroxyurea is that it can be quite toxic, suppressing the bone
marrow and causing problems such as neutropenia, mouth ulcers
and hair loss.
People adding hydroxyurea to their ddI-containing regimen may
experience a greater reduction in viral load because of the
increased antiviral effects, but any CD4 count rise may be
smaller because of hydroxyurea's toxic effects on blood cells.
BOX 1: HOW DOES IT WORK?
Hydroxyurea doesn't attack HIV directly, but instead it works
indirectly to boost the effects of ddI.
Human cells use an enzyme called ribonucleotide reductase to
make the building blocks of their genetic material, DNA. In
HIV-infected cells, HIV uses the same building blocks to
assemble its own genetic material. NRTI drugs such as AZT and
ddI work by mimicking these building blocks, tricking HIV into
building its DNA with the drug rather than with a real building
Hydroxyurea inhibits ribonucleotide reductase, reducing the
number of normal building blocks within the cell. This makes it
more likely that an HIV-infected cell will use an NRTI block
rather than a real block, increasing the chance of interrupting
Since it affects a cell enzyme, rather than an HIV enzyme,
there may be less chance for resistance to develop to
hydroxyurea, compared with anti-HIV drugs.
There is also preliminary evidence suggesting that hydroxyurea
may have other beneficial effects, such as encouraging the
death of HIV-infected cells through a process called apoptosis.