Sixth International Conference, Part III: Toxoplasmosis
The Conference news on Toxoplasma gondii infections largelyconsisted of refinements in diagnosis and a growing
acknowledgement of the value of prophylaxis for people at risk
for toxoplasmosis. Although the Conference published abstracts
of more than twenty studies of this infection, no truly new
therapies available for use were among them.
Jack S. Remington, M. D. of Stanford University presented
the Conference's oral session on toxoplasmosis management, and
opened his discussion by commenting on the low priority assigned
thus far to combatting this major problem. Following is a survey
of his remarks and selected studies from the Conference
abstracts.
Toxoplasmosis usually, but not exclusively, presents as
symptoms of encephalitis or neurologic difficulties. Computerized
tomography (CT) scans are often used to screen possible causes of
neurologic symptoms, but they are not always reliable for
distinguishing the lesions of Toxoplasma from those of lymphoma,
Kaposi's sarcoma, PML, CMV or herpes. Magnetic resonance imaging
(MRI) is more useful, and brain biopsy or aspiration the most
conclusive.
To avoid losing critical time until a diagnosis is
absolutely certain, treatment for cerebral masses is often
initiated under the presumption of toxoplasmosis; a good response
to the treatment becomes a marker for an accurate diagnosis. But
not every case responds, and meanwhile some other cause of the
symptoms may have progressed untreated. An example of lymphoma
misdiagnosed as toxoplasmosis was mentioned in AIDS TREATMENT
NEWS #104. A Conference abstract from Rio de Janeiro described
how an increase in the number of presumptive toxoplasmosis
diagnoses for cerebral masses was accompanied by an increase in
deaths of patients who did not respond to toxoplasmosis
treatment. The authors cite the need for better criteria for
presumptive diagnosis of this infection (abstract #2115, Sohler,
MP and others).
Dr. Remington pointed out that the retina, GI tract,
pancreas, heart and lungs have been reported as sites of
infection as well, so toxoplasmosis must be approached as a
possibly disseminated infection. He added that he and American
and French colleagues have developed better methods (differential
agglutination) of testing Toxoplasma titers, but they can only
wait for private industry to make these widely available.
A study from the University of Miami and New York University
reported four instances of congenital Toxoplasma infections in
infants born to mothers who were seropositive for both HIV and
toxoplasmosis (abstract #F. B. 476, Mastrucci, M and others).
This information could be helpful for pediatricians trying to
diagnose encephalitis in newborns, since two of the mothers in
the study had no history of active toxoplasmosis. The infants
were born with HIV as well.
The treatments discussed in the oral session included the
standard regimen combining pyrimethamine with sulfadiazine, as
well as agents under study: clindamycin, dapsone, doxycycline,
566C80, gamma interferon and a class of drugs called macrolide
antibiotics, which include roxithromycin, azithromycin,
spiramycin and clarithromycin. (An important note for
researchers regarded the importance of different strains of
Toxoplasma. Since this variable often determines the agents to
which the protozoa will be susceptible, a number of strains
should be subjected to a given compound, in research studies.)
When sulfa drugs cannot be tolerated, recent clinical
practice has been to replace sulfadiazine with clindamycin. Dr.
Remington said that the combination of clindamycin with
pyrimethamine is generally considered effective, but no evidence
yet proves it equal or superior to pyrimethamine with a
sulfonamide. IV clindamycin offers more data so far than oral
clindamycin.
Doxycycline, which has shown positive results against
Toxoplasma in animal data, did not control toxoplasmic
encephalitis in humans, according to doctors at Elmhurst Hospital
Center in New York. Their abstract was a chart review of six
patients who had shown intolerance to treatment with sulfadiazine
and pyrimethamine, and who were then given doxycycline for at
least one month. Five of the six experienced a return of lesions
during therapy. Three of those five responded to retreatment
with the standard drugs (abstract #TH. B. 479, Turett, G and
others). We were hoping for more success with doxycycline,
perhaps in some combination therapy if not by itself, for people
who cannot continue with sulfadiazine. A related study from
Sidney described the successful desensitization to sulfadiazine
in some people known to have sulfa allergies by giving gradually
increasing increments of the drug over several days. Of sixteen
patients with toxoplasmosis, ten were reported to be desensitized
(abstract #TH. B. 480, Tenant-Flowers, M and others).
Of the macrolide antibiotics, azithromycin looks the best in
mice studies. To control Toxoplasma, a drug must reach
significant concentrations in body tissues and not just blood.
Azithromycin is exceptionally effective in this regard. Dr.
Remington pointed out that azithromycin's strong potential as a
toxoplasmosis therapy has been common knowledge for over two
years, and not a single controlled human trial of the drug has
yet been conducted.
566C80 is a new agent from Burroughs-Wellcome with strong
activity against Toxoplasma, perhaps including the capacity to
kill the parasite's cysts. This compound is also under study to
treat Pneumocystis infections. Clinical studies of this drug are
planned by the NIH.
Gamma interferon, which is probably the body's prime natural
defense against Toxoplasma, has been shown to have additive or
synergistic effect with some antibiotics -- namely clindamycin,
roxithromycin and pyrimethamine. (On the other hand, AZT may
block the activity of pyrimethamine in mice, underscoring the
need for access to more than one anti-HIV drug for people
requiring treatments for opportunistic infections.) ACTG trials
of gamma interferon to treat toxoplasmosis are being developed.
An abstract from the University of Genoa described Septra as
an effective alternative to pyrimethamine and sulfadiazine for
treating toxoplasmosis (abstract Th.B. 477, Canessa, A and
others).
Trimetrexate, under investigation to treat Pneumocystis
infections, also has strong in vitro activity against Toxoplasma.
Authors of a Belgian abstract emphasized the importance of
environmental precautions for people who are HIV+ but who test
negative for toxoplasmosis. They advise their patients to avoid
gardening, exposure to cat feces, and eating raw meat or uncooked
vegetables (abstract F. B. 426, Liesnard, C and others). People
whose blood tests show evidence of a latent Toxoplasma infection
could of course also benefit from those precautions, as well as
the use of some preventive therapy to thwart a reactivation. Dr.
Remington mentioned that there are no data solidly supporting a
particular toxoplasmosis prophylaxis.
But recently, Septra, clindamycin and pyrimethamine have
been suggested as candidates for clinical prophylaxis trials. A
study from Spain described success with Fansidar in lowering the
incidence of toxoplasmosis (abstract #2116, Iribarren, JA and
others). Fansidar may have unacceptable risks, however, since it
has been linked to some fatal allergic reactions. Another chart
review at Elmhurst Hospital found that patients who were taking a
double-strength tablet of trimethoprim-sulfamethoxazole (Septra
or Bactrim) twice a day to prevent Pneumocystis pneumonia
experienced a lower incidence of toxoplasmosis than patients on
aerosol pentamidine (abstract Th.B. 482, Nicholas, P and others).
After an episode of toxoplasmosis is treated, some
suppressive therapy must be continued since no drug tested in
humans has been able to kill the oocysts (resting forms of the
organism) which can produce live parasites again in people with
compromised immunity. Researchers in Barcelona have found that
pulse-dosing, or intermittent maintenance treatment, of
pyrimethamine and sulfadiazine twice a week effectively prevented
relapses of active infections in fifteen patients. (A similar
finding was presented last year at the Montreal conference).
This could help many people who cannot tolerate the toxicity of
daily dosing. However, other experts have cautioned that the
half-life of pyrimethamine can vary from person to person, so
pulse-dosing may be reliable for persons whose bodies retain such
a drug long enough, and not for others. Incidentally, in the
comparison groups of the study's participants who could be
followed, fifteen patients decided, against medical advice, to
not continue with any maintenance therapy. Eight of those
developed a relapse of toxoplasmosis between two to fifteen
months after their first episode. Ten other participants tried
intermittent treatments of pyrimethamine with clindamycin,
instead of sulfadiazine. Unfortunately, four of them experienced
a relapse after two to nine months (abstract TH. B. 483,
Gonzalez-Clemente, JM and others).
In spite of the good efforts and intentions evident in all
of these studies, people are still dying of toxoplasmosis.
Survival is better with early diagnosis and concurrent anti-HIV
therapy, but even given these advantages something less toxic and
more effective than pyrimethamine with sulfadiazine is needed.
Dr. Remington spoke for many when he expressed frustration with
the static situation of treatment research for this infection.
For example, more than a year ago an update on toxoplasmosis in
AIDS TREATMENT NEWS (#79) included a report on arprinocid, at
that time considered one of the most promising compounds to be
laboratory tested against Toxoplasma. We could find no mention
of arprinocid at this Conference, nor of trimetrexate, nor of any
human experience with azithromycin, as Dr. Remington noted.
If arprinocid, azithromycin, 566C80, gamma interferon, or
trimetrexate are not safe or useful in humans, we need to know.
And if they are safe and effective, we need to know that too, as
soon as possible.
source: AIDS Treatment News
