TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies; Volume 5 Number 3 -- March 28, 1991
Gabriel Torres, M. D.

Background

Toxoplasmosis of the central nervous system (CNS) is one of the most common life threatening opportunistic infections (OIs) in people with AIDS. A brain disorder which occurs in 25-30% of PWAs, toxoplasmosis is the reactivation of a previous infection. Exposure and re-exposure to Toxoplasma gondii, the parasite which causes the infection, often happens by eating undercooked meat or by coming in contact with contaminated cat feces. Approximately 30-40% of the general adult population are infected with, and consequently develop antibodies against Toxoplasma gondii. Studies have demonstrated that nearly one-third of AIDS patients, who have been exposed previously to toxoplasnia, will develop toxoplasmosis within two years of their diagnosis of AIDS (1).

The most common symptoms of the infection are confusion, headaches, fever, paralysis, seizures, and difficulty seeing, speaking and walking. Untreated, the infection can lead to progressive lethargy (lack of energy), coma and even death. The most important factors in preventing the complications of toxoplasmosis are early recognition of symptoms, prompt initiation of treatment, and lifelong suppressive therapy to prevent the recurrence of brain abscesses.

Standard Therapies

The mainstay, and currently most effective therapy for toxoplasmosis, is the combination of pyrimethamine (Daraprim) and sulfadiazine. Unfortunately, 40-60% of patients develop drug reactions which require discontinuation of this therapy. The most common of these side effects are skin rashes and leukopenia (low white blood cell counts). Clindamycin, a similar drug, is often substituted for sulfadiazine in patients with sulfa allergy.

One retrospective study showed that 11 of 15 patients treated with clindamycin had clinical improvement and resolution of brain lesions caused by toxoplasmosis (2). But the side effects of clindamycin often preclude its use as a chronic therapy. Toxicities include diarrhea, skin rashes, and abdominal pain. Clindamycin has also been associated with the development of colitis (inflammation of the colon from an overgrowth of bacteria) and bloody diarrhea.

In one study, a group of Spanish researchers reported that 16% (7/43) of patients died within the first week of treatment for toxoplasmosis, regardless of treatment regimen. Fifty percent of the patients who recovered after 21 days of treatment with pyrimethamine/sulfadiazine chose not to continue maintenance therapy and relapsed after an average of 12 months (3). None of the patients on maintenance therapy (twice weekly pyrimethamine/sulfadiazine) relapsed after an average follow-up period of 10 months. However, 40% (4/10) of patients on pyrimethamine/clindamycin maintenance therapy relapsed in this study. And in a similar study reported in France, two of six patients relapsed on the same regimen (4).

Clarithromycin (Klacid)

Clarithromycin is a macrolide antibiotic which has been shown to inhibit the growth of Toxoplasma gondii in the test tube. In studies using the blood cells of mice, clarithromycin eradicated infection in 42% of the cells with disseminated lethal toxoplasmosis (5,6). In a human trial, twelve patients received clarithromycin at 2000 mg daily and pyrimethamine at 75 mg daily for six weeks. Nine patients (75%) showed total or partial resolution of brain lesions and a striking clinical response after six weeks of treatment (7). The high dose of clarithromycin was well-tolerated except for mild hearing loss. Additional adverse effects were attributable to other medications which patients were then taking. There are no clinical trials in the U. S. using clarithromycin for toxoplasmosis. The sponsor, Abbott Pharmaceuticals, is currently under pressure from AIDS activists to establish a compassionate use program for the drug as a treatment for Mycobacterium-avium intracellulare (MAI). Abbott also needs to consider a protocol for salvage therapy (when standard treatments fail) of toxoplasmosis.

Azithromycin

Azithromycin is another macrolide antibiotic which has been shown to have potent anti-toxoplasma activity in mice (8). At doses of 200 mg/kg administered daily for 10 days the drug protected 80% of mice infected with toxoplasnia. Azithromycin has a very long half-life (50-90 hours) in humans and penetrates well into tissues and cells. This makes the drug an excellent agent for oncedaily or intermittent dosing. Both azithromycin and clarithromycin have activity against MAI and could be used for prophylaxis against both infections. The AIDS Clinical Trials Group (ACTG) has finalized a protocol using azithromycin and pyrimethamine for acute treatment of toxoplasmosis (9). The trial is being conducted at Cornell Medical Center; contact Evie Gassyuk-Botev, R. N. at (212) 746-4177. Pyrimethamine will be used initially but the drug will be tapered off during the course of treatment. Azithromycin is also available from the sponsor, Pfizer, under a compassionate use protocol for patients who have failed or are intolerant of pyrimethamine, sulfadiazine, or clindamycin. Physicians can obtain the drug by contacting Dr. Michael DeBruin at (203) 441 5701.

566c80

This drug, originally tested against malaria, is also active against a variety of parasites, including those that cause toxoplasmosis, PCP and cryptosporidiosis. In animal experiments, 566c80 has been shown to protect mice against death due to infection with five different strains of toxoplasma (10). Burroughs Wellcome, the sponsor of this compound, is testing it in a clinical trial with patients who are either failing standard therapy for toxoplasmosis with pyrimethamine/sulfadiazine or patients who have developed intolerance to one of the standard treatments. The trial is being conducted at St. Vincent's Hospital in New York. For more information, contact Michael Thorn, R. N., at (212) 790-8319.

Gamma Interferon

Gamma Interferon is a cytokine (immune modulating protein) used by Dr. Jack Remington in experiments with mice infected with toxoplasma. It has been shown to be effective in eradicating infection. Antibodies to gamma interferon can induce toxoplasmosis in immunosuppressed mice, indicating that the cytokine plays a crucial role in killing the parasite in the cell. A phase II trial of gamma interferon in addition to clindamycin and pyrimethamine is recruiting at Cornell Medical Center for patients who have failed or are intolerant to standard therapies. Call Evie Gassyuk-Botev, R. N. for more information, at (212) 746-4177. Another clinical trial using gamma interferon in combination with pyrimethamine/sulfadiazine in patients with toxoplasmosis is expected in the near future.

Bactrim/Septra and Fansidar

Bactrim and Septra are two versions of the same drug. Bactrim is made by Hoffmann-La Roche, and Septra is made by Burroughs Wellcome. These two drugs are a combination of trimethoprim and sulfamethoxazole. Animal studies have shown that Bactrim/Septra is less active than sulfadiazine and pyrimethamine. One report from Italy showed that 18 of 25 patients with cerebral toxoplasmosis responded to intravenous Bactrim/Septra (11). Further controlled studies are needed to evaluate this combination in the treatment and prophylaxis of toxoplasmosis. Sulfa allergies will again pose a problem for the majority of patients with AIDS.

In a small trial in France, 29 of 36 HIVpositive patients with toxoplasmosis improved while using Fansidar, a sulfa-based drug made by Hoffmann-La Roche. However, five participants suffered recurrences of infection after two to six weeks of maintenance treatment. The most common adverse effect during this trial was skin rash.

Toxoplasmosis prophylaxis

Several clinical trials are investigating various drugs in the primary prevention of toxoplasmosis in persons with HIV who have dormant or latent infection. A person can have blood tests to detect the presence of antibodies to Toxoplasnia gondii. The Community Program for Clinical Research on AIDS (CPCRA) is comparing clindamycin to pyrimethamine in a randomized placebo-controlled study, conducted at several centers in New York (call 1-800-TRIALS-A). Another trial being conducted at Cornell Medical Center is comparing pyrimethamine alone at a dose of 50 mg three times weekly to placebo in persons with toxoplasma antibodies. For information call (212) 461-4177. Yet another retrospective study showed that Bactrim/Septra at a dose of one double-strength tablet twice daily was effective in preventing toxoplasmosis (12). Other drugs with potential anti-toxoplasmic activity, which may be useful in prophylaxis, include dapsone, roxithromycin, Fansidar and 566c80. [See Treatment Issues, Vol. 4, No. 1.]

Conclusion

Though progress has been slow in the development of new drugs for toxoplasmosis, several new agents have recently shown excellent activity in mice and are now ready for clinical testing in humans. The most urgent need is determining which is the safest, most effective agent to prevent toxoplasmosis in persons with HIV infection. It is anticipated that if these new agents prove useful as salvage therapies, they will rapidly enter into prophylaxis trials since they have potential to prevent more than one opportunistic infection.

Footnotes:

1 Grant H et al. Toxoplasma gondii serology in HIVinfected patients: the development of CNS toxoplasmosis in AIDS. AIDS 4:519-521,1990.

2 Dannemann BR et al. Treatment of toxoplasma encephalitis with intravenous clindamycin. Arch Intern Ned 148:2477-2452, 1988.

3 Pedrol E, et al CNS toxoplasmosis in AIDS patients: Efficacy of an intermittent maintenance therapy. AIDS 4:511-517, 1990.

4 Leport C et al. An open study of the pyrimethamine/clindamycin combination in AIDS patients with brain toxoplasmosis. J Infect Dis 160:557, 1989.

5 Chang HR et al. In vitro effects of four macrolides (roxithromycin, spiramycin, azithromycin and A-56268) on Toxoplasma gondii. Antimicro Agents and Chemo 32:524-29, 1988.

6 Chang HR et al. Activity of A-56268, a new macrolide against Toxoplasma gondii in mice. J Antimicro Chemo 22:359-61, 1988.

7 VIth Internat Conf on AIDS, oral presentation, Catherine Leport, M. D.

8 Araujo FG. Azythromyacin, a macrolide antibiotic with potent activity against T. Gondii. Antimicro Agents and Chemo 32:755- 57,1988.

9 ACTG Trial #156.

10 Araujo FG et al. Remarkable in vitro and in vivo activities of the hydroxynaphtboquinone, 566c80 against tachysoites and tissue cysts of T. gondii. Antimicro Agents and Chemo 35:293- 99,1991.

11 VI Internat Conf on AIDS, abstract THB. 477, San Francisco, June 1990.

12 VI Internat Conf on AIDS, abstract ThB. 482, San Francisco, June 1990.

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