TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies, Vol 5, No. 2, - Feb 25, 1991
Victoria Nott

Fungi, one-celled yeast-like organisms also cause infections with great frequency in people with AIDS. Fungal diseases are usually chronic, sometimes severe conditions, which often recur after initial treatment. The most common diseases caused by fungi found in people with AIDS are cryptococcal meningitis, candidiasis (thrush), and histoplasmosis. Other fungal diseases have been seen in people with AIDS, but this article will focus on the prevention of these three diseases.

Background

There have been important treatment advances for fungal infections in the last few years with the development of a new class of drugs called "azoles." Azole drugs come in many forms. Topical azoles are drugs that are applied directly to the infected area. Miconazole (Monistat), clotrimazole (Mycelex) and ketoconazole (Nizoral) are topical drugs which are currently available on the market. Nystatin (Mycostatin) is another topical drug, prepared either as a lozenge called a troche for oral fungal disease, or as a vaginal insert for vulvovaginal yeast infection.

Oral antifungal drugs, including ketoconazole, fluconazole (Diflucan) and flucytosine (Ancobon), are commonly administered for disseminated (body-wide) fungal infection. Flucytosine, however, seems to cause the rapid growth of resistant strains of fungi, and so is sometimes given in combination with other antifungal drugs (11). Patients taking oral azoles need to be monitored for possible liver toxicity.

Standard therapy for serious fungal disease has been with amphotericin B (Fugizone), the first antifungal drug approved. Amphotericin B is available only intravenously and is sometimes supplemented with oral flucytosine, although there is no consensus about the benefits of adding flucytosine. Amphotericin B is highly toxic. For long-term use, it is usually administered through a catheter (a tube surgically implanted to allow direct administration of drug into the blood stream).

The approval of fluconazole for treatment of cryptococcal meningitis and serious candidiasis is a tremendous step forward because of the drug's low toxicity and availability in pill form. When taken orally, fluconazole can cross the "blood-brain barrier," unlike amphotericin, and has proven to be at least as effective as amphotericin (12).

Antifungals as Prophylaxis

People with HIV infection who develop serious fungal disease must generally stay on lifelong maintenance therapy at a reduced dose. Currently, there is interest in the possibility of

preventing fungal disease from occurring in the first place. While there is no consensus about the ability of azoles to prevent a first outbreak of fungal disease, Dr. William Powderly of Washington University, St. Louis, Principal Investigator of antifungals for the National Institute of Allergy and Infectious Diseases (NIAID), says, "Most of us probably feel this is the way to go, but prophylaxis has not yet been proved safe or effective." With the incidence of life-threatening fungal disease occurring in about 5% of people with AIDS, as opposed to about 50% for PCP, it is much harder to pinpoint who should receive prophylaxis, said Powderly. For instance, it may not be worth the possible toxicity and cost to prescribe prophylaxis for cryptococcal meningitis for everyone under a certain T4 cell count. Since serious side effects are relatively rare with azoles, the more important question may be the exorbitant price charged for certain antifungal drugs, like fluconazole, which is made by Pfizer.

The Resistance Debate It is possible that long-term use of antifungal drugs might result in resistance to the drug. Resistance has been a problem with AZT, ganciclovir (therapy for cytomegalovirus, or CMV) and acyclovir (therapy for herpes infections). However, Dr. Powderly believes that resistance to azole drugs is more theoretical than practical.

Other doctors are more conservative and express some caution about the use of fluconazole, for instance, as prophylaxis. Dr. Abigail Zuger of Montefiore Hospital in the Bronx, New York, believes that resistance could become a problem when using antifungals as prophylaxis. She expressed concern over a recent report of cryptococcus that became resistant not only to fluconazole but also to amphotericin B after fluconazole was administered. The history of antibiotics includes many instances of organisms developing resistance in response to prolonged use of one drug. Some researchers fear that premature prophylactic use of antifungal drugs may diminish the usefulness of such hopeful new drugs as fluconazole.

Cryptococcal Meningitis

Cryptococcus neoformans is a one-celled yeastlike organism which can cause a body-wide infection in people with immunosuppression. This infection is thought to be acquired by inhaling fungus into the lungs. Avoidance of this kind of fungus may be difficult, since many people are unaware of exposure. Cryptococcal organisms have been found in many natural sites, including weathered pigeon droppings. Once inhaled, the fungus grows in colonies, infecting the lungs and possibly spreading to the brain. Infection of the brain can cause cryptococcal meningitis, a serious disease that occurs in approximately 10% of all AIDS patients and is fatal in nearly 60% of those infected (13,14,15).

The two antifungal drugs used for treatment of cryptococcal meningitis are amphotericin B and fluconazole. One clinical trial provides some evidence that amphotericin B may be superior to fluconazole for initial treatment of cryptococcal meningitis (16). However, the same study shows that fluconazole may be better at controlling relapses (17).

It is commonly agreed that any immunosuppressed person who has had cryptococcal meningitis should take maintenance therapy indefinitely to avoid relapses of disease. Often the choice for maintenance therapy is fluconazole. A few skin rashes and two cases of thrombocytopenia (low platelet count) have been reported with prolonged use of fluconazole. In the trial using fluconazole as a prophylaxis for cryptococcal meningitis, Dr. Powderly has observed no severe side effects. Nearly 15% of patients in the trial had nausea, which either improved with time or was controlled by administering smaller doses of drug twice a day, rather than the whole amount at once.

Presently, there is only one federally funded trial for prophylaxis of cryptococcus (18). Nearly 360 subjects will take either 200 mg of fluconazole daily to protect the whole body from infection, or they will receive clotrimazole lozenges to protect against oral symptoms. Some participants have been enrolled for as long as a year already, and reports from study coordinators indicate that the trial is "going well." It will be another year before there is any information about the efficacy of these drugs in preventing fungal diseases.

Candidiasis (Thrush)

Candida albicans is a fungus that causes candidiasis, which is common and can occur in a variety of places in and on the body. The most frequent breeding ground for candida is in the mouth, where it is commonly referred to as thrush. Thrush is a very frequent condition in HIV infection, which has been seen in up to 60% of AIDS patients (19). Thrush can appear as creamy white or yellowish patches in the mouth, which sometimes can be scraped off, or as red splotches in the mouth. The infection may also entail cracks at the corners of the mouth and a sore throat. Oral thrush may progress and cause further infection in the throat, esophagus, and intestinal tract. For women, vaginal thrush, an odorous white, creamy infection of the vulva and/or vagina, may precede oral thrush.

Oral thrush responds well to local treatment with clotrimazole troches. Miconazole or clotrimazole are used as intravaginal creams or suppositories for vaginal yeast. For more widespread cases, systemic treatment is with oral ketoconazole or fluconazole (20).

Some medical professionals recommend antifungal maintenance therapy indefinitely for severe thrush or vaginal candidiasis. Although some resistance to fluconazole has been observed in people with thrush, it does not seem to be a common occurrence. Dr. Zuger of Montefiore Hospital finds topical Mycelex to be an adequate treatment for most cases of thrush and vaginal candidiasis.

Not much work has been done to prevent thrush. One approach currently being tested for oral infection is treatment with a rinse, called Peridex. The active ingredient in Peridex, which is used by dentists for gum disease, is chlorhexidine, a disinfectant that kills candidal organisms in the test tube. Procter & Gamble, the maker of Peridex, is conducting placebo- controlled trials at five sites in order to determine if washing with the prescription mouthwash two to three times daily will delay or prevent oral thrush in HIVpositive people with a history of this condition. The study, which was announced last June, is scheduled to last six months. Dr. Deborah Greenspan, DDS, investigator at the University of California, San Francisco, reported that about 20 patients are already enrolled at the site. Since the study is blinded, no data is yet available. Additionally, at the dental clinic of St. Clare's Hospital, New York City, Peridex is being tried in an unblinded pilot study of 20 patients. The aim of this study is to determine if Peridex, which is much less expensive than topical medications such as Mycelex and Nystatin, is effective as a maintenance therapy. Dr. Stephen Able of St. Clare's reports that Peridex seems to help some patients but not others. For information about enrolling in this Peridex trial, contact Dr. Able at (212) 459-8327.

Histoplasmosis

Histoplasma capsulatum is a yeast that causes histoplasmosis, a disease which may be asymptomatic, mild or severe. Histoplasmosis can be an elusive infection, affecting many parts of the body, including lungs, lymph nodes and bone marrow. It usually causes a cough, fever, and general malaise. In the U. S. infection seems to be more common in the southeastern, midatlantic and midwestern states. In regions where histoplasmosis is common, infection occurs in 5-10% of patients with AIDS (21).

One trial reported that oral ketoconazole was effective in suppressing histoplasmosis for up to two years after initial treatment with amphotericin B (22). Two of ten patients relapsed during the ketoconazole trial (one at six months, and one at 21 months) and were retreated with amphotericin B. Another trial reported successful treatment of histoplasmosis with itraconazole (Sporanex), which is not approved yet in the U. S. (23). Lastly, there was one report of successful maintenance therapy with fluconazole, after initial treatment with amphotericin (24).

Currently there are two federally-funded trials to study the effects of itraconazole, which is similar to fluconazole, but does not cross the "blood-brain barrier," which limits itraconazole's potential as a treatment for cryptococcal meningitis. Both of the federally-funded trials, one complete and the other still recruiting patients, are for HIV-infected persons with a history of histoplasmosis to determine whether itraconazole is effective in preventing relapses of disease. Because histoplasmosis is fairly rare in the northeast, New York area and New Jersey hospitals, participating in the trial, report small numbers of patients enrolling.

Dr. Kathleen Squires of Cornell Medical Center did report that one trial, which is now closed, had eight patients enrolled at the site (25). None of them had any relapses of histoplasmosis while taking itraconazole.

Dr. Joseph Wheat, a principal investigator of the itraconazole trials, reports that the drug shows promise for both acute treatment and maintenance therapy of histoplasmosis. There were no relapses in any of the 33 patients who could be evaluated from the trials. And nearly 25 patients treated with itraconazole for first episodes of histoplasmosis yielded "encouraging" results. The U. S. manufacturer of itraconazole, Janssen Pharmaceuticals, is reportedly seeking approval from the Food and Drug Administration (FDA) to market the drug, and a data review is expected soon.

A new trial, currently recruiting patients for a one year study of itraconazole as a treatment for histoplasmosis, will try to determine if itraconazole can prevent disease from returning (26). Patients will take itraconazole daily for 12 weeks and those who do well on it will continue for another year. To enroll or get more information in the New York City area, contact the following people: Patrice Edwards, Albert Einstein College of Medicine at (212) 430-3659; Robert Winters, Cornell Medical Center at (212) 584-9000, ext. 1169; Mercedes Rios, Montefiore Hospital at (212) 920-6563; Brenda Kolatch, St. Luke's/Roosevelt Hospital at (212) 523-6722; or Grace Ouma, Robert Wood Johnson Medical School in New Brunswick, New Jersey at (201) 937-8571.

Itraconazole is available by prescription outside the U. S. The People With AIDS Health Group, an underground buyers' club in New York, reports that a healthy supply of itraconazole is available by calling (212) 532-0280. According to a representative of the buyers' club, it is a "popular drug" with clients.

Antifungals on the Horizon

Schering Corporation is developing another new antifungal drug of the "triazole" class for treatment and maintenance therapy of cryptococcal meningitis and thrush. Two hundred patients worldwide have been treated with this drug, which is called "SCH 39304." The drug is considered to be quite similar to fluconazole, and many fear that those fungal strains resistant to fluconazole may also be resistant to SCH 39304. One recent report from a small open-label trial claims a 43% response rate in patients with cryptococcal meningitis approximately the same rate seen for amphotericin B and fluconazole.

Dr. Belle Lee, at San Francisco General Hospital, one site where SCH 39304 is being tested, reports that the drug works at least as well as ketoconazole for thrush. The drug reportedly stays in the body somewhat longer than fluconazole does, and so will require less frequent dosing, said Dr. Lee. The side effects are minor. Data for SCH 39304 are being assembled and will be presented in June at the International Conference on AIDS. Approval and availability of this new drug may help to lower the price of fluconazole.

An efficacy trial for oral SCH 39304 in people with cryptococcal meningitis is currently recruiting patients (27). Participants will take drug for 12 weeks, and, for those who respond to treatment, random assignments will be made for drug once a week or once a day for up to a year. For more information call 1-800-TRIALS-A.

Additionally, a less toxic form of amphotericin B which incorporates a lipid coating is being tested for efficacy in people with cryptococcal meningitis. A double-blind, dose comparison study funded by The American Foundation for AIDS Research (AmFAR) will compare amphotericin B with this less toxic formation called, amphotericin B lipid complex. All participants will receive fluconazole for 12 weeks after finishing six weeks of drug. For further information about this trial, which is currently recruiting patients, contact Wendie Lubin at (212) 420- 4041 at Beth Israel Medical Center in New York, or Nancy Pietroski at (215) 925-8010, Pennsylvania Hospital, Philadelphia.

Conclusion

There are, of course, many unanswered questions about the efficacy and safety of antifungal drugs as prophylaxis. Secondary prophylaxis with maintenance therapy is definitely recommended after initial treatment of systemic fungal infection for people who are HIV-infected. There is a need for primary prophylaxis for common fungal infections, but none of the candidate drugs has been proven safe and effective as a standard preventive measure. There is some feeling among community physicians that fluconazole prophylaxis is advisable for persons with T4 cell counts under 100, as a strategy to prevent multiple fungal infections. It is hoped that more solid data will be presented at the Seventh International Conference on AIDS in Florence this June.

Footnotes:

9 CDC, AIDS weekly surveillance Report-U. S., P. S, 0ctober S, 1987.

10 CDC, HIV/AIDS Surveillance, Year-End Edition, p. 16, January 1991.

11 Braunwald E et al. Harrison's Principles of Internal Medicine. 11th Edition, p. 737,1987.

12 Sugar A et al. 0verview: Treatment of Cryptococcal Meningitis. Rev Inf Dis 12:5338-5348, March-April, 1990.

13 Kovacs JA et al. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med. 103: 533-538, 1985.

14 Eng RH et al. Crytococcal infections in patients with AIDS. AM J Med. 81:19-23,1986.

15 Zuger A et al. Cryptococcal disease in patients with AIDS. Ann Intern Med. 104:234-40, 1986.

16 Larsen RA et al. Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS, Ann Intern Med 113:183-87, 1990.

17 ibid, pp 177-179.

18 ACTC Trial #981 is a separate arm of FCP prophylaxis trial 081.

19 Kaplan MH et al. Dermatolofflc findings and manifestations in AIDS. J Am Acad Derrnatol 16:486-506, 1987.

20 Meunier F et al. Therapy for oropharyngeal candidiasis in the immunocompromised host: a randomzed doubleblind study of fluconasole vs. ketoconasole. Rev Inf Dis 12, Supp 3:5364- 368,1990.

21 Larsen R. Asoles and AIDS. J Inf Dis 163: 727-730, 1990.

22 Vth Internat Conf on AIDS, abstract MBP. 80, Montreal, June, 1989.

23 ibid, MBP. 81

24 ibid, MBP. 79

25 ACTG trial # 084.

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