Hydroxyurea
by Mark Bowers
Combinations of antiretroviral drugs have led to remarkable decreases
in the amount of HIV in the blood, as measured by viral load assays. The
drugs that are selected for combination regimens include nucleoside analog
drugs (AZT, ddI, ddC, d4T and 3TC), non-nucleoside reverse transcriptase
inhibitors (nevirapine and delavirdine) and protease inhibitors (saquinavir,
ritonavir and indinavir). These 3 classes of drugs target 2 HIV enzymes
-- reverse transcriptase and protease, respectively.
Experience has shown that HIV enzymes mutate in response to treatment
with antiretroviral drugs. The state in which HIV is no longer susceptible
to a specific antiretroviral drug is called resistance to that drug. Resistance
involves the creation of new types of HIV called "escape mutants"
that can thrive even in the presence of powerful antiretroviral drugs.
Resistance emerges very quickly when only one antiretroviral drug is used,
and more slowly or not at all when combinations are used.
Current strategies to control HIV infection are based on reducing the
number of HIV particles in the blood to as low a number as possible, preferably
to undetectable levels as measured by the currently available HIV viral
load tests. It is thought that significantly reducing the number of HIV
particles in the body delays the development of resistance and the emergence
of escape mutants.
Historical Perspective
Franco Lori, MD, of the Research Institute for Genetic and Human Therapy
in Europe, and others have recently described a second strategy for reducing
levels of HIV. Drugs like hydroxyurea (Bristol-Myers Squibb, brand name
Hydrea) target enzymes that are made by human cells instead of by HIV.
Hydroxyurea inhibits the enzyme ribonucleotide reductase and, in so doing,
reduces the numbers of DNA building blocks known as deoxyribonucleotides
that are available in an infected cell. Nucleoside analog drugs work by
replacing deoxyribonucleotides with drug molecules. These drug molecules
are similar to naturally occurring deoxriboynucleotides, but since their
structure is slightly different, they either interfere with viral DNA
production or produce defective viral DNA.
Hydroxyurea effectively disrupts DNA synthesis in rapidly dividing cells
and reduces the number of deoxyribonucleotides so that there are not enough
building blocks to make functional viral products. A cell with insufficient
deoxyribonucleotides will resort to using synthetic building blocks to
complete DNA synthesis, so more nucleoside analog drug molecules are taken
up and metabolized. Therefore, a combination of hydroxyurea and one or
more nucleoside analog drugs would be expected to result in a large reduction
in viral load.
Hydroxyurea has been used for more than 30 years in the treatment of
leukemia, melanoma and ovarian cancer, and has recently attracted attention
as a potential agent for treating sickle cell anemia. It was licensed
by the Food and Drug Administration (FDA) before 1982. There have never
been any reports of resistance to the drug. The earliest report of possible
use of hydroxyurea in controlling HIV replication was published in 1987.
Since then, sporadic reports of test-tube experiments done in various
laboratories around the world have appeared in the literature. Intensive
investigation of hydroxyurea began in Robert Gallo's Tumor Cell Biology
Laboratory at the National Cancer Institute.
Lori sparked the initial widespread interest in using hydroxyurea for
HIV at the December 1993 National Conference on Human Retroviruses and
Opportunistic Infections. He reported that hydroxyurea inhibited HIV replication
in peripheral blood mononuclear cells and macrophages, reservoirs of HIV
infection that are unaffected by currently approved antiretroviral drugs.
Inhibition was shown to occur at doses lower than those usually used for
cancer chemotherapy. The combination of hydroxyurea plus ddI (Videx) produced
a synergistic effect in cells taken from HIV positive individuals.
A pilot study of the combination of ddI and hydroxyurea, conducted by
Larry Mole, MD, and Mark Holodniy, MD, at the AIDS Research Center in
Palo Alto, CA, was initiated in December 1994. Previous clinical studies
indicated that HIV viral load suppression is not as pronounced in people
with fewer than 250 CD4 cells/mm3. Several other clinical studies
have since looked at the combination of hydroxyurea plus d4T or AZT plus
ddI. Most of this research has been conducted in Europe.
Side Effects
The side effects of hydroxyurea are dependent on the dose and are more
frequent at the higher doses used in cancer chemotherapy. Bone marrow
suppression, one of the more frequent side effects, makes hydroxyurea
inappropriate for people with anemia (low red blood cell counts), thrombocytopenia
(fewer than 100,000 platelets, cells required for normal blood clotting)
or neutropenia (low white cell counts). Less frequent side effects include
anorexia, nausea, vomiting, diarrhea and constipation. Rashes, particularly
on the face, have also been reported. At least one report mentions alopecia
(unwanted hair loss) when higher doses of the drug are used (1,000 mg
twice daily).
Hydroxyurea is relatively inexpensive. The drug was listed in the 1996
Physicians' GenRx at $687.76 for a 252-day supply at two 500 mg tablets
per day. Because of its known hazard to unborn children, hydroxyurea should
not be used by pregnant women.
Clinical Studies
Several small studies of hydroxyurea in combination with ddI or d4T have
been concluded. In 1994, Franco Lori's 24-week study of hydroxyurea plus
ddI compared with ddI monotherapy revealed a 1.3-log decrease in plasma
viremia in 40 participants after 2 to 4 weeks on combination therapy.
The decrease was stable throughout the 24-week observation period. Those
on ddI monotherapy saw initial viral load decreases that quickly returned
to pre-treatment levels.
A 1-year French study of 20 volunteers with CD4 cell counts greater than
181 cells/mm3 evaluated CD4 cell increases and viral load decreases
in response to the combination of hydroxyurea (500 mg twice a day) and
ddI (200 mg twice a day). After 180 days in the study, the average increase
in CD4 cells was 117 cells/mm3. Eleven volunteers achieved
undetectable viral load levels (as measured by the Roche Amplicor test,
which has a limit of detection of 200 copies/mL). After 360 days, 6 persons
still had undetectable levels of virus. Lymphoid tissue studies were also
done on these 6 volunteers, and could detect no infectious virus.
A Canadian study of 26 volunteers with 100-300 CD4 cells/mm3
compared the effects of 500 mg daily of hydroxyurea to 1,000 mg daily.
Both groups were also taking ddI. Julio Montaner, MD, and colleagues at
the British Columbia Centre for Excellence in HIV/AIDS, monitored the
CD4 cell count and viral load in volunteers who received ddI alone for
1 month, then ddI in combination with either 500 mg or 1,000 mg of hydroxyurea
for 1 month, then only ddI for 1 month. No differences were noted in CD4
cell counts between the 2 groups, but 3 of 13 on 500 mg daily of hydroxyurea
experienced statistically significant decreases in viral RNA load, while
6 of 13 on 1,000 mg daily of hydroxyurea experienced similar decreases.
Recently, a 12-week Swiss study of 142 people with an average CD4 count
of 350 cells/mm3 compared the combination of ddI plus d4T to
ddI plus d4T plus hydroxyurea. Those on the 3-drug combination achieved
RNA viral load reductions of 2.2 log after 12 weeks, compared to an average
1.8-log reduction for those on the 2-drug combination. CD4 cell count
increases were reversed in magnitude for the 2 groups. Those taking triple
combinations experienced an average increase of 91 cells/mm3,
while those on the double combination experienced an average increase
of 10 cells/mm3. Of those on the triple combination, 55% experienced
viral load decreases to below the 200-copies/mL limit of detection, while
32% of those on the double combination reached undetectable viral load
levels.
Use of hydroxyurea alone does not result in increases in CD4 cell counts.
The mechanism proposed for the drug partly explains why there are no increases:
cellular replication is decreased while, at the same time, viral replication
is held in check. Opinions differ about whether inhibiting cellular replication
has beneficial or detrimental long-term implications.
Current Clinical Studies
Several clinical studies of hydroxyurea in combination with antiretroviral
drugs are open now. Shared Medical Research Foundation in Tarzana, CA,
is evaluating the safety and preliminary efficacy of hydroxyurea alone
or in combination with ddI or ddI plus d4T. Participants may not have
had pancreatitis (a side effect of ddI) within the past 2 years, or have
an active opportunistic infection requiring treatment during the study.
Participants also may not have used d4T or ddI before, nor may they have
taken any experimental drug within 21 days of participating in the study.
The study lasts 68 weeks. For more information, call Shared Medical Research
Foundation at 818-345-2172.
The American Foundation for AIDS Research (AmFAR) network of study sites
is conducting a study of the safety and antiretroviral activity of hydroxyurea
plus ddI in 80 people who have never used ddI before. Hydroxyurea is started
at different times relative to when ddI therapy is started. Eligibility
requirements include a viral load of greater than 10,000 copies/mL and
a CD4 count between 60-500 cells/mm3. Participants will take
one 500 mg capsule of hydroxyurea twice a day and one of 2 doses of ddI,
depending on body weight. The study lasts 24 weeks. For more information,
call 1-800-TRIALS-A.
Conclusions
While encouraging, the results of completed clinical studies leave unanswered
the questions of which dose of hydroxyurea is most appropriate and for
whom. Several groups from the United States, Canada, Spain, Italy and
France have now provided data lending support to earlier reports that
hydroxyurea is ineffective as monotherapy.
The best indications are that hydroxyurea is most appropriate and effective
early in HIV disease -- at least before CD4 cell counts drop below 250
cells/mm3. The most studied dose is 500 mg twice daily, a dose
that appears to be associated with few side effects. A higher dose of
1,000 mg twice daily was associated with greater bone marrow toxicity
and some hair loss.
Researchers clearly still have much work to do before they can make definitive
recommendations about the use of hydroxyurea to decrease HIV viral load.
Furthermore, Bristol-Myers Squibb has expressed scant interest in pursuing
an HIV indication for hydroxyurea with the FDA. But for those individuals
who seek an alternative to protease inhibitors in their combination antiretroviral
therapy, or for those for whom such combinations have failed, hydroxyurea
may be an option.
Mark Bowers is Managing Editor of Treatment Publications at the San
Francisco AIDS Foundation.
Extensive research for this article was done by Diane Cenko, a director
of the Andrew Ziegler Foundation in San Francisco.
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Page last updated 1 April 1997
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