GMHC Treatment Issues 1998 Jul/Aug 1; 12(7/8): 2
Several significant developments related to hydroxyurea (HU)
were discussed at the 12th World AIDS Conference in Geneva. A
new clinical trial confirmed the capacity of the triple-drug
combination regimen of ddI/d4T/HU to substantially reduce HIV
viral loads in na�ve patients. Two laboratory studies showed
that HU enhances the activity of some of the nucleoside analogs
(AZT, 3TC and d4T) through its effect on another cellular
enzyme that is involved in the activation of these drugs.
Another laboratory study demonstrated that HU increases the
capacity of two new drugs, adefovir and PMPA, to achieve viral
suppression, even with virus known to be multidrug resistant.
Finally, a retrospective study analyzing patient experience
found that patients with advanced HIV can benefit from
therapies that include HU. All these intriguing reports plus
the general feeling that new therapeutic strategies are needed
to overcome the limitations of existing drugs made hydroxyurea
a popular subject of conversation at Geneva.
International ddI/d4T/Hydroxyurea Study
Dr. Sergio Lupo, from Argentina, presented the results of an
international randomized controlled study comparing the triple
combination ddI/d4T/HU to other anti-HIV combinations (abstract
12235). The study, which was carried out in Argentina, Brazil,
Canada and Mexico, enrolled 183 treatment-na�ve patients into
one of the following four arms: ddI/AZT; ddI/d4T; ddI/HU; or
ddI/d4T/HU. The HU dose was 500 mg twice a day. Baseline
characteristics were as follows: CD4 counts between 200 and 500
cells/mm3, with median count of 345; median viral load of
33,000 copies/ml; median age of 30, and 68% were male.
At the time of the report, 75% of the patients had completed 24
weeks of treatment, and viral load results were available for
118 patients. Mild-to-moderate side effects including nausea
and vomiting were reported in all the study arms, with a higher
incidence in the AZT/ddI arm. At week 24, 76% of the patients
in the ddI/d4T/HU arm had undetectable viral load (below 400
copies/ml), against 53% in the ddI/d4T arm, 43% in the ddI/HU
arm, and 36% in the AZT/ddI arm. These differences are
statistically significant. Mean drop of viral load in the
triple-combination arm was reported to be 2.0 logs (99%).
Changes in the absolute CD4 counts were minimal in the
HU-containing arms, compared to some increases in the ddI/d4T
and AZT/ddI arms.
Enhanced Activity of Nucleoside Analogs
Dr. Franco Lori, from the Research Institute for Genetic and
Human Therapy (RIGHT) of Washington, D.C., and Pavia, Italy,
has indicated that RIGHT's future research protocols for
HU-based combinations will include d4T as well as ddI. Dr. Lori
and RIGHT were the original promoters of hydroxyurea research.
Dr. Lori and other researchers at the Geneva conference
presented a new theory to explain the additional benefit of
this triple combination over the ddI/HU double combination.
Hydroxyurea, which is known to inhibit the activity of the
cellular ribonucleotide reductase enzyme, may also indirectly
increase the activity of another group of cellular enzymes. The
ribonucleotide reductase enzyme is responsible for the creation
of the nucleotide pools that serve as building blocks for both
cellular and HIV genes. Ribonucleotide reductase is especially
important for the creation of adenosine, for which ddI serves
as a defective replacement. By inhibiting the action of
ribonucleotide reductase, HU slows the creation of new HIV
genes as the virus attempts to infect a new cell.
The other cellular enzymes that HU may affect are responsible
for the conversion of the nucleosides and defective nucleoside
analogs such as AZT, d4T, 3TC and ddC into the active compounds
in a process known as "phosphorylation." When the nucleoside
pools are depleted by the action of HU, cells appear to enhance
the activity of these enzymes, making more activated nucleoside
analogs available inside the cell to stop viral replication.
In a World AIDS Conference satellite session sponsored by
Bristol-Myers Squibb (producer of HU as well as of d4T and
ddI), Dr. Jean-Pierre Sommadossi, from the University of
Alabama at Birmingham, presented the results of a
phosphorylation study in which CD4 cells were taken from
patients who had been on long-term (3 to 4 years) nucleoside
analog therapy and were failing. These cells were exposed to
d4T and HU in the test tube, and the results showed a three- to
four-fold increase in d4T phosphorylation when HU was present,
regardless of the nucleosides to which the patient had been
exposed in the past. (Last winter, Dr. Sommadossi reported the
results of experiments indicating that prolonged exposure to
AZT reduces cells' phosphorylation of that drug, and of d4T as
Another Conference report (abstract 42262) described the
results of a study at the Pharmacology University of Liverpool
(U.K.) that investigated the effects of HU on the activation of
nucleoside analogs AZT, 3TC and ddI. The study found a
significant increase in the phosphorylation of 3TC and AZT in
the presence of HU.
Hydroxyurea and Adefovir, PMPA: Promising Results in the Lab
One of the most interesting studies that supports the use of HU
in combination with the nucleotide analogs adefovir and PMPA
(both made by Gilead Sciences) was presented at the 2nd
International Workshop on HIV Drug Resistance and Treatment
Strategies, which took place in Lake Maggiori, Italy, just
before the Geneva Conference. In the study (see abstract 3 of
the Resistance Workshop), researchers from Stanford University
Center for AIDS Research measured the IC50 of adefovir, PMPA,
and ddI, alone and in the presence of HU. (The IC50 is the drug
concentration needed to reduce HIV activity in cell culture by
half. This value goes up as the virus becomes more
drug-resistant; a reduction means the drug is becoming more
effective.) They measured the IC50 of these compounds for a
wild-type laboratory isolate of HIV, and for two clinical
ddI-resistant isolates known to be multidrug resistant. The
concentrations of HU used in the study were low and correspond
to what would be clinically tolerated in the body.
Researchers compared the IC50 values for these three drugs
alone with the IC50 values when HU was added. The results were
as follows: when HU was added to ddI, a seven-fold reduction on
ddI IC50 occurred with the wild-type HIV. A 17-fold and a
22-fold reduction were observed in the comparatively high ddI
IC50 for the two multidrug-resistant isolates. With adefovir,
the reductions were eight-fold (with the wild-type isolate),
four-fold and five-fold (with the multidrug-resistant
isolates). The HU-associated reductions for PMPA were 26-fold
with the wild-type and 6-fold and 35-fold with the
multidrug-resistant HIV strains.
The Stanford lab results support the design of clinical studies
using adefovir or PMPA in combination with HU. They also
confirm results from previous clinical studies of ddI/HU, in
which suppression of the virus continues despite the presence
of ddI-resistant HIV mutations. The Center for AIDS Research at
Stanford University is currently enrolling patients whose HIV
has specific reverse transcriptase and protease gene mutations
in a trial of a quadruple-drug combination with adefovir,
efavirenz, ddI and HU (see Treatment Issues, June 1998).
Hydroxyurea in Salvage Therapy
Steven Miles, from the UCLA Care Center, presented the results
of an open-label retrospective study (Geneva abstract 12205) of
18 heavily treated patients with advanced HIV (median CD4 count
of 63 and median viral load of 427,325 copies/ml). They had all
received at least 8 weeks of therapy with d4T/3TC/HU. These
patients had clinical and genotypic resistance to d4T and 3TC.
Dr. Miles reported a median peak 1.7 log (98%) viral load
reduction at week 8 on these patients. A median weight gain of
4.3 kg was observed. Severe bone marrow suppression was common:
four patients required blood transfusions, five patients
required erythropoietin to increase red blood cell counts, and
four others received G-CSF to increase their population of
neutrophils (a type of infection-fighting white blood cell).
The average length of time with at least a .7 log reduction was
17 weeks. The benefits of this HU regimen seem transient in
advanced patients with a history of poor response to other
Despite the temporary nature of the response, large number of
adverse effects and widespread skepticism, Dr. Miles is very
positive about the results. He stresses that it is unheard of
to get such a large viral load reduction in persons similar to
this cohort, whose HIV contained a large number of mutations
associated with drug resistance. As for the side effects, Dr.
Miles thinks that many of these can be attributed to other
drugs the patients were or had been taking.
Long-term ddI/HU -- the "Panda" Patients
New virologic and immunologic data were presented on 12 of the
57 patients in the original ddI versus ddI/HU study conducted
by RIGHT. These 12 individuals have now been followed for an
average of 2.5 years in the double-combination therapy.
Researchers have named members of this cohort the "Panda"
patients because of their limited number. They started with an
average viral load of 51,795 copies/ml. Their viral load
decreased gradually, and at week 122 the average remains at 254
copies/ml for the eight patients with measurable HIV (using the
quantification limit of 200 copies/ml), with no rebound despite
the presence of ddI-resistant virus. The average increase in
CD4 counts has been only 40 cells.
Most importantly, Dr. Lori reported that 6 of the 12 trial
participants exhibited HIV-specific CD4 cell responses. These
responses have not been found in other patients whose viral
load is fully suppressed with HAART, except those treated
during initial, or primary, HIV infection. (The "Panda"
patients started treatment during chronic stable infection, not
during the initial period just after contracting HIV.) In fact,
one of the main subjects of the Conference was the lack of such
responses, and potential mechanisms to induce them.
ACTG-307 -- Results are in
It took a long time for the U.S. National Institutes of Health
AIDS Clinical Trials Group to enroll its ddI/HU trial. Results
from this study were presented at the ACTG meeting held August
1-4, 1998. This clinical trial compared ddI/HU for six months
versus ddI alone for three months, with HU added for the second
three months. Complete results were not available at press
time, but our sources indicate that very good results were
achieved in the combination arms with both the 1,000 mg and
1,500 mg daily doses of HU. The 1,500 mg arm fared slightly
better, but as expected there was more toxicity associated with
this high dose. Viral load reductions in the ddI/HU arms were
similar in both na�ve and experienced patients. This was not
the case in the ddI monotherapy arm, where experienced patients
did much worse than na�ve patients. This is consistent with the
results from other studies showing ddI-resistant virus is still
sensitive to ddI in the presence of HU.
ACTG-307 participants will have the opportunity to roll over to
a new trial in which they will choose to either add a new agent
or stay in the ddI/HU combination. The ACTG is also planning
rollover studies from several other ACTG trials that will
include HU-containing regimens. Regimens that contain
hydroxyurea plus adefovir, PMPA or d4T/3TC also are under ACTG
Robert Murphy, from Northwestern University in Chicago, is
leading a clinical trial comparing ddI/d4T/efavirenz to
ddI/d4T/efavirenz/HU. Participants can be experienced or na�ve.
Those in the HU arm will start with ddI/d4T/efavirenz for four
weeks to raise the CD4 counts, before adding HU to the
combination. This trial, which is funded by Bristol-Myers
Squibb (BMS), is due to start next month in sites across the
U.S., France and Canada.
New Size Pills Available for Dosing Studies
Contrary to the usual new drug development process, clinical
research of HU as an HIV therapy has proceeded before an
optimal dose has been determined. No dose escalation study has
been performed, essentially because, until recently, the drug
was only available in the 500 mg size. This June, BMS started
producing HU in 200 mg, 300 mg and 400 mg pills. These new
pills will allow for further flexibility in dosing quantities
and schedules. However, they are significantly more expensive.
Dr. Lori has a new study (RIGHT 702) to look at dosing amounts
and intervals, specifically when used with ddI/d4T. The
objective of this trial is to determine what the smallest daily
dose of HU can be and still be effective. It will also provide
information as to whether taking HU once a day is as good as
twice or three times daily. The study has nine arms, with all
patients on ddI and d4T at dosages related to their weight.
There will be three total daily amounts of HU: 1,200 mg (once a
day, 600 mg twice a day or 400 mg three times a day); 800-900
mg (800 mg once a day, 400 mg twice a day or 300 mg three times
a day); and 600 mg (once a day, 300 mg twice a day or 200 mg
three times a day). Patients are required to have a viral load
of less than 50,000 copies/ml. The cohort will be 75%
treatment-na�ve and 25% drug-experienced.
This study will provide information that is crucial to
physicians who are either already prescribing HU to some of
their patients, or are planning to do so in the near future.
Based on current data, most doctors usually prescribe HU at 500
mg twice a day. One of the first studies done by Julio Montaner
in Canada suggested that a daily dose of 500 mg of HU had a
lesser impact on viral load reduction than the 1,000 mg daily
dose. Doses above 1,200 mg a day, on the other hand, generally
have a greater incidence of side effects.