TREATMENT ISSUES, Volume 6, Number 6 - July, 1992; The Gay Men's Health Crisis Newsletter of Experimental AIDS Therapies
Gabriel Torres, M.D.

Toxoplasmosis

The treatment and prevention of toxoplasmosis, a serious infection of the brain, has received much more attention abroad than it has in the U.S. As PCP rates declined in Europe, toxoplasmosis cases sky rocketed, especially in the southern European countries, such as Spain, France, and Italy. Therefore, large clinical trials have been conducted, seeking convenient, effective strategies against the parasite that causes the infection, Toxoplasma gondii. The European Network for the Treatment of AIDS (ENTA) conducted a multicenter trial comparing the standard treatment for toxoplasmosis, sulfadiazine and pyrimethamine, to a treatment alternative used in people with sulfa allergies, pyrimethamine and clindamycin.[1] In this randomized, open study, 342 people with an initial episode of toxoplasmosic encephalitis (inflammation of the brain) were assigned to one or the other of the treatment regimens. Of those participating, 77% had either a complete or partial response to sulfadiazine / pyrimethamine, compared to 68% who responded to pyrimethamine / clindamycin. This difference was not statistically significant; therefore, both treatments appear to be equally effective in treating toxoplasmosis. The most common side effects of sulfadiazine/ pyrimethamine were rashes and fever. These side effects caused 31% of participants taking sulfadiazine / pyrimethamine to switch to the other treatment. An equivalent percentage of participants taking pyrimethamine/ clindamycin switched over to the other treatment due to side effects, the most common of which were diarrhea and fever. Only one patient in the sulfadiazine/ pyrimethamine group had to switch over to the other treatment due to a lack of response and a worsening condition. However, 20 of the 37 participants taking pyrimethamine / clindamycin had worsening conditions due to failure of the treatment, and had to switch over to the other regimen.

A second study investigated azithromycin and pyrimethamine as a combination therapy against toxoplasmosis. Azithromycin is a fairly new antibiotic from the macrolide family, which has shown activity against Toxoplasma gondii in experiments with mice. Dr. Joseph Saba of France investigated the use of 500 mg/day of azithromycin and 75 mg/day of pyrimethamine in patients with toxoplasmosis. Fourteen patients were enrolled, but four had to discontinue the treatment after three weeks due to side effects. The response was evaluated in ten patients who completed 21 days of therapy. Five had better than 50% improvement in symptoms and a reduction in the size of toxoplasmic brain lesions. One patient had a partial response. Two patients had worsened conditions or no change in their condition. Two patients were not able to be evaluated. The most ~t*m~side effects were fever and rash, vomiting, elevated liver enzymes, and hearing impairment. The overall feeling was that the combination of azithromycin and pyrimethamine was slightly inferior to the response rates which have been demonstrated with sulfadiazine and pyrimethamine, but that further studies were required using participants who could not tolerate other drugs.

Finally, 566C80, an antimalarial drug, was found to be effective in a small group of participants with toxoplasmic encephalitis who failed or were intolerant of standard therapy. The original study was conducted in the U.S. at the National Institutes of Health. Burroughs Wellcome is developing a larger open trial of 566C80 as salvage therapy, but the final results are not available yet. In the meantime, a group of investigators from Belgium and France used the drug as a first choice therapy in 28 patients.2 Of the 28 participants, 23 completed six weeks of treatment at a dose of 750 mg four times daily. Thirteen patients (56%) saw a disappearance of their brain lesions or a significant decrease in the size of their lesions. Only two patients saw no change in their condition after 42 days of treatment, although they remained in stable condition. Side effects included elevated liver enzymes in ten patients, rash in six patients, and gastrointestinal problems in four. The response rate of 566C80 was slightly inferior to that of the standard therapy, but 566C80 remains a promising agent as an alternative treatment for people who fail standard therapy. Because the drug is also active against the organism that causes PCP, further investigation of this concerning prophylaxis against both infections is urgently needed. A new oral formulation of 566C80 which is thought to be absorbed better should be available soon for future trials.

Prophylaxis for PCP and Toxoplasmosis

Various European studies evaluated trimethoprim / sulfamethoxazole (Bactrim/Septra), dapsone/pyrimethamine and aerosolized pentamidine (AP) as a prophylaxis against PCP and/or toxoplasmosis. One large Swiss study compared a weekly dose of dapsone (200 mg)/pyrimethamine (75 mg) to aerosolized pentamidine once monthly in 364 patients with T4 cell counts under 2~0.[3] Five cases of toxoplasmosis occurred in these participants (one in the dapsone/pyrimethamine group and four in the AP group). One case of PCP occurred in the AP group. Unfortunately, 26% of the participants in the dapsone/pyrimethamine group had to discontinue the drugs due to side effects (fever and rashes) compared to only 2% of participants taking aerosolized pentamidine. Another Spanish group of investigators compared Bactrim/Septra three times weekly, AP (300 mg once monthly) and dapsone (100 mg)/ pyrimethamine (25 mg once weekly).[4] All three treatments were effective in preventing a first episode of PCP, but pentamidine was the best tolerated.

A similar comparative trial of dapsone (50 mg/day) versus fansidar (1 tablet per week) showed similar effects in preventing both PCP and toxo- plasmosis.[5] A poster presentation compared Bactrim to dapsone and found that Bactrim tended to be better in preventing bacterial infections and PCP in injection drug users (IDUs).[6] One study of AP in children (ages 5 months - 7 years) showed that the drug was not as effective as Bactrim.[7] The overall European experience demonstrates that Bactrim and the combination of dapsone and pyrimethamine can prevent both PCP and toxoplasmosis. Therefore, they may be the preferred prophylaxis regimens since they can prevent both infections, whereas AP has no activity against toxoplasmosis.

Cryptococcal Meningitis

Cryptococcal meningitis is a fungal infection that causes serious brain disease. Standard medicine is with intravenous amphotericin, a highly toxic drug. At the European conference, an Italian group studied a different version of the same drug which is coated with a fatty covering, making the drug less toxic to the body.[8] The drug is called liposomal amphotericin, and its brand name is Ambisome. Seven patients with cryptococcal meningitis were treated with the drug. Within two weeks, four participants responded with a decrease in the number of cryptococcal organisms in the cerebrospinal fluid (CSF) and an improvement of symptoms. Two participants remained completely free from infections for six months, although two had a recurrence of infection in the prostate gland. Two patients had a moderate response to the treatment, and one failed. The only side effect was nausea in one participant. This is a dramatic divergence from the usual side effects of amphotericin B, which are fever, chills, and kidney dysfunction. Such side effects, in fact, have been reported to occur in 100% of patients. Liposomal amphotericin is a welcome addition to fungal treatment.

A French study compared fluconazole to amphotericin B in the treatment of cryptococcal meningitis.[9] The effectiveness of amphotericin B was 80%, compared to 76% with fluconazole. Amphotericin B remains the treatment of choice for cryptococcal meningitis in the U.S., although fluconazole can be used for mild episodes of disease.

Mycobacterium avium complex (MAC)

Several posters described small trials of clarithromycin in combination with either clofazimine or ciprofloxacin/amikacin in patients with disseminated MAC. This AIDS-defining illness is a complicated grouping of bacteria that causes severe disease late in the course of HIV disease. In a small French study, clarithromycin (2 gms/day) and clofazimine (200 mg/day) were used for two months and then the doses were reduced by 50%.[10] In 14 of 17 patients, blood samples showed that no MAC bacteria remained after only one week of therapy, and, after four months of therapy, the 14 patients were still on treatment and surviving. Only one patient stopped treatment due to liver toxicity. No relapses or resistance developed. In the second study from Italy, clarithromycin was used in combination with amikacin and ciprofloxacin in ten patients.[11] In all cases, fever disappeared within one week and blood samples tested negative for MAC bacteria in six of the seven cases. No patient had to stop treatment due to toxicity. These two small trials are very encouraging and provide some groundwork for the use of combination clarithromycin regimens in the treatment of MAC infection. It is still unclear whether the same results can be obtained using clarithromycin as a single-agent treatment.

Microsporidiosis and Cryptosporidiosis

Various European researchers have investigated new ways of diagnosing microsporidiosis, a severe diarrhea-causing infection that is prevalent in many AIDS patients with gastrointestinal symptoms. A group from France has developed a method of diagnosing microsporidiosis by direct microscopic examination of stool.[12] This method seems to be as effective as microscopic examination of biopsy tissue from the small bowel, which requires an endoscopy, a procedure that is invasive and uncomfortable. Other researchers reported that microsporidia in the biliary tree (passages for bile to flow in the liver) and the gall bladder may be the cause of common biliary obstruction that often leads to infection (cholangitis) in people with AIDS.[13]

Another interesting study compared azithromycin, letrazuril, and paromomycin (Humatin) as treatments for people with cryptosporidial diarrhea.[14] Azithromycin (500 mg/daily) was determined to be completely ineffective in the treatment of cryptosporidiosis. Letrazuril (50 mg/day) seemed to kill the disease-causing organisms in the stool, but did not reduce the amount of diarrhea. Paromomycin (500 mg daily) improved symptoms in the majority of patients, but did not remove the organisms from stool or biopsy. Another new drug called aminoside sulfate, which had previously demonstrated anticryptosporidial activity in the test tube, was tested in five French patients with cryptosporidiosis.[15] Four of the five patients had a resolution of diarrhea and the number of organisms in the stool was reduced, making the drug a promising potential treatment for cryptosporidiosis.

Conclusion

European scientists seem to be quite advanced in the treatment and research of AIDS-related opportunistic infections. These results are all promising, in that they offer people with HIV and AIDS some new understanding, hope, and clarity about treatment. The ACTG and other U.S. research forces must follow suit in prioritizing research efforts that contribute to the enhancement and quality of life for people with HIV/AIDS. The prevention of OIs must become a priority for U.S. researchers.

References:

1. III European Conf on AIDS, Abstract #019, Paris, March, 1992.

2. III European Conf on AIDS, Abstract #04~, Paris, March, 1992.

3. III European Conf on AIDS, Abstract #034, Paris, March, 1992.

4. III European Conf on AIDS, Abstract #035, Paris, March, 1992.

5. III European Conf on AIDS, Abstract #036, Paris, March, 1992.

6. III European Conf on AIDS, Abstract #P99, Paris, March, 1992.

7. III European Conf on AIDS, Abstract #044, Paris, March, 1992.

8. III European Conf on AIDS, Abstract #027, Paris, March, 1992.

9. III European Conf on AIDS, Abstract #P182, Paris, March, 1992.

10. III European Conf on AIDS, Abstract #243, Paris, March, 1992.

11. III European Conf on AIDS, Abstract #P41, Paris, March, 1992.

12. III European Conf on AIDS, Abstract #030, Paris, March, 1992.

13. III European Conf on AIDS, Abstract #031, Paris, March, 1992

14. III European Conf on AIDS, Abstract #P28, Paris, March, 1992.

15. III European Conf on AIDS, Abstract #P175, Paris, March, 1992.

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