AIDS TREATMENT NEWS No. 108 - August 3, 1990
Denny Smith

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, J.A. 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, J. M. 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.

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