Gay Men's Health Crisis Treatment Issues, Vol. 5, No. 7 - October, 1991
Gabriel Torres, M.D.

PROPHYLAXIS FOR CRYPTOCOCCAL MENINGITIS

A few studies were presented at the International Conference on AIDS in Florence, Italy to support the use of the anti-fungal drugs, fluconazole (Diflucan) and ketoconazole (Nizoral), as means for preventing widespread fungal infection in HIV-positive individuals. One study by Peterson and others from the University of Texas Southwestern Medical School reported promising results by comparing patients taking fluconazole to an historical control group of patients. The study compared 289 HIV-positive patients with T4 counts under 68 who received fluconazole (100 mg/day) to 366 patients, who did not receive fluconazole prophylaxis.[1] One fungal infection (disseminated cryptococcosis) developed in the fluconazole patients, and 20 infections (14 cryptococcosis and 6 histoplasmosis) occurred in the control patients.

Another study from Brazil compared a group of 78 AIDS patients who received ketoconazole (200 mg/day) to 95 patients who received no antifungal therapy.[2] During the follow-up period, there were no cases of cryptococcal meningitis (CM) in the patients taking ketoconazole, but eight cases of CM in control patients. No patient had to discontinue ketoconazole due to toxicity. The most frequent complaints of patients taking [the] drug, included nausea during the first month of therapy and a rise in liver enzymes which proved to be reversible.

Twenty-one patients died in the ketoconazole group, but of the 15 on whom autopsies were performed, none had fungal organisms. This suggest that death was probably not due to fungal infection. In the group that did not receive ketoconazole, there were 32 deaths. Of the 21 patients on whom autopsies were performed, three had fungal organisms. The authors postulate that even though ketoconazole does not penetrate well into the cerebrospinal fluid (CSF) and directly affect the brain, it may still prevent dissemination of fungus from the lungs.

An earlier study presented by Dr. Howard Aronow suggested that ketoconazole was effective in preventing cryptococcosis.[3] Of the 210 HIV-infected men who were given ketoconazole in this study, none developed infection, whereas 11 of 91 patients, who were not receiving prophylaxis, developed disease. In addition, only five patients experienced toxicities which required withdrawal of the drug.

PROPHYLAXIS FOR THRUSH

Oral thrush is a very frequent condition, which generally occurs early in HIV infection in persons with relatively high T4 cell counts. However, widespread thrush, including involvement of the esophagus, trachea and bloodstream, tends to occur in patients with more advanced disease and lower T4 counts.

Involvement of the esophagus often leads to ulcerations, painful swallowing and marked weight loss. The treatment of thrush often depends on the severity of the infection. Thrush of the esophagus usually requires systemic therapy with ketoconazole (Nizoral), fluconazole (Diflucan) or amphotericin B.

A recent randomized double-blind trial compared fluconazole (100 mg/day) to ketoconazole (200 mg/day) in 143 patients with thrush in the esophagus.[4] The fungus was eradicated in 91% of the patients on fluconazole, as compared to only 52% of patients on ketoconazole. Symptoms such as difficulty swallowing and chest pain resolved in 85% of the fluconazole patients compared to 65% of the ketoconazole patients. It is noteworthy that most physicians continue prophylaxis with either ketoconazole or fluconazole therapy in patients who have sustained a bout of esophageal thrush, in order to prevent a relapse.

In another placebo-controlled study oral thrush was prevented by fluconazole (100 mg/day) among patients with a history of recurrent thrush.[5] Thrush occurred in none of the patients on fluconazole compared to eight of 13 patients who received a placebo. Other agents which may be useful for prophylaxis of oral thrush are clotrimazole troches (Mycelex), Nystatin suspension or tablets and Peridex mouth rinses.

PROPHYLAXIS FOR HISTOPLASMOSIS

A report from Texas showed that fluconazole was not effective in preventing histoplasmosis in two patients with AIDS.[6] Whether itraconazole, a new anti-fungal drug for preventing relapse of disease, will prove effective in preventing initial bouts of histoplasmosis among patients in endemic areas remains to be seen.

RESISTANCE

Uncontrolled studies suggest that either fluconazole or ketoconazole may be beneficial in preventing initial fungal infections. However, Many professional are still concerned that widespread use of these drugs may lead to the development of resistant strains of fungi. Resistance means that new forms of fungus will develop in the body which are not killed by the drug usually used to control infection. Two studies presented in Florence demonstrated that the fungus which causes thrush became resistant to fluconazole after prolonged therapy.

In a study from France, of the 28 patients with AIDS or ARC, 17.85% developed relapses of oral thrush while on fluconazole (50 mg/day).[7] Another report from Scotland studied three patients who had persistent signs and symptoms of oral thrush, despite treatment with fluconazole (150 mg/day, for one year). None of the three responded to higher doses of drug (200 mg/day) and all patients required treatment with amphotericin B and flucytosine (another anti-fungal treatment regiment). These cases illustrate that resistance can develop in patients maintained on long-term anti-fungal therapy, and such resistance impairs the use of the drugs when needed for treatment of acute infection.

FUNGAL INFECTION AND T4 COUNTS

Most prophylactic regimens can claim success when the OIs for which they are prescribed can be definitively linked to T4 counts. For example, it is now standard therapy to use PCP prophylaxis when an HIV-positive individual's T4 counts reach about 200 cells. Occurrences of PCP have been found to be clearly related to T4 counts under 200. However, when other OIs occur in relation to T4 cell counts, they are not as clearly defined. One Australian study published in the Journal of AIDS reviewed the occurrences of OIs in a retrospective study of 185 patients. [8]

According to the study, esophageal thrush and cryptococcal meningitis occurred in patients with T4 counts between 75-125. According to a different study, cryptococcal pneumonia occurred in patients with T4 counts under 200.[9] Another French study by Isabel Lacomte, presented in San Francisco in 1990, showed that systemic cryptococcal disease almost always occurred in patients with T4 counts under 100. It is therefore reasonable to assume that most cases of systemic fungal infection will occur when T4 counts fall below 100, and that prophylaxis should be considered at this point. However, when to begin antifungal prophylaxis will remain controversial until more studies of resistance to antifungal drugs, cost-effectiveness of prophylaxis, and naturally [sic] history of OIs are completed.

REFERENCES

1. VIIth Internat Conf on AIDS, abstract #W.B. 2279, Florence, June 1991.

2. VIIth Internat Conf on AIDS, abstract #W.B. 2307, Florence, June 1991.

3. Aronow H et al. Neurological manifestations of HIV infection. In AIDS 90 Summary, Philadelphia Sciences Group, Richmond, VA, 244.

4. VIIth Internat Conf on AIDS, abstract #W.B. 2317, Florence, June 1991.

5. VIth Internat Conf on AIDS, abstract #2165, San Francisco, June 1990.

6. VIIth Internat Conf on AIDS, abstract #W.B. 2360, Florence, June 1991.

7. VIIth Internat Conf on AIDS, abstract #W.B. 2357, Florence, June 1991.

8. Crow SM et al. Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in HIV-infected persons. J AIDS 4:770, 1991.

9. Masur H et al. CD4 counts as predictors of opportunistic pneumonias in HIV infection. Ann Intern Med 111:223, 1989.

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