Opportunistic Infections Research - National Institute of Allergy and Infectious Disease
AIDS-RELATED FUNGAL ILLNESSES
Acquired immunodeficiency syndrome (AIDS), a life-threatening disease of the immune system, has become a worldwide epidemic since 1981, the year it was first identified. In the United States alone, an estimated 1 million Americans are infected with the human immunodeficiency virus (HIV), the virus that causes AIDS; more than 150,000 persons have been diagnosed with AIDS, and more than 100,000 deaths have been attributed to it.
Persons infected with HIV may have no symptoms for years, but the eventual destruction of the immune system by HIV makes them vulnerable to infectious agents that rarely cause illness in individuals with intact immune defenses. As a result, HIV-infected persons are particularly susceptible to the development of opportunistic infections (OIs), which include a variety of viral, fungal, bacterial, and protozoal diseases. Fungal OIs are common and some can be life-threatening for those with advanced HIV infection. AZT (zidovudine, Retrovir, the only approved anti-HIV drug, can delay the onset of these infections, but does not prevent them. Consequently, safe and effective therapies are needed to prevent and treat OIs.
The National Institute of Allergy and Infectious Diseases (NIAID) has the principal responsibility in the federal government for research on AIDS. A major focus of the NIAID program is the development and evaluation of promising drugs for treating and preventing the OIs associated with AIDS, including various fungal infections.
NATURE OF THE FUNGAL DISEASES
One of the most frequently occurring fungal diseases in persons with HIV infection is thrush, or candidiasis, caused by the organism Candida albicans. The appearance of thrush is the most common sign that HIV infection is entering an advanced symptomatic stage and is predictive of the development of AIDS. One form of candidiasis, which affects the mucous membranes in the mouth and throat, produces a sore throat. Women with HIV infection may experience vaginal candidiasis, which causes a discharge and local discomfort. Infants may experience candidiasis as a severe form of diaper rash. A more serious form of candidiasis is esophageal candidiasis, which causes pain and difficulty in swallowing, and interferes with eating. While debilitating and uncomfortable, candidiasis is rarely a life-threatening complication of HIV infection.
Cryptococcus neoformans, a yeastlike fungus, can cause infections of the skin, lungs, and meninges (the membranes that surround the brain and spinal cord). The most common form of cryptococcal infection in AIDS patients is meningitis, a life-threatening infection of the central nervous system.
Histoplasmosis is a fungal infection commonly acquired in the midwestern United States and the Caribbean. In persons with AIDS, inhaled or ingested spores of Histoplasma capsulatum can cause symptoms of an acute pneumonia or influenza-like illness. Infection can spread throughout the body, especially to the meninges, the heart, and the adrenal glands.
Persons with AIDS are also susceptible to infections caused by various other fungal organisms. Among these infections, which occur less frequently than those described above are coccidioidomycosis and aspergillosis.
MAGNITUDE OF THE PROBLEM
Serious, life-threatening fungal infections eventually affect between 10 and 20 percent of all persons with AIDS. To date, few therapies are effective in preventing such infections.
Thrush, or oral candidiasis, is found in almost all persons with advanced HIV infection and my lead to esophageal candidiasis.
Cryptococcal infections have been reported in 2 to 13 percent of persons with AIDS. Cryptococcal meningitis accounts for two-thirds of these cases. If untreated, cryptococcal meningitis is fatal, and 50 to 90 percent of the individuals who respond to treatment subsequently relapse if treatment is not maintained for life.
In midwestern areas of the United States, 5 to 10 percent of persons with AIDS develop disseminated histoplasmosis. In the Southwest, coccidioidomycosis is the third most common OI in AIDS patients.
Persons with fungal diseases often respond initially to standard therapies approved by the Food and Drug Administration (FDA). Unfortunately, the fungal infection frequently recurs in these persons treatment is continued indefinitely (lifelong maintenance or suppressive therapy).
Clotrimazole (Mycelex, as a slow-dissolving tablet held in the mouth, or mycostatin, as a solution that is swished around in the mouth and then swallowed, have each been used to combat oral candidiasis. Possible side effects of clotrimazole include nausea, vomiting, diarrhea, and an increase in liver enzymes; possible side effects of mycostatin include diarrhea gastrointestinal upset, nausea, and vomiting.
Ketoconazole, a drug that can be taken by mouth, has been given for esophageal candidiasis but may not be well absorbed by persons with AIDS, who often have decreased stomach acid. Ketoconazole also has been used to prevent recurrence of disseminated histoplasmosis in persons with AIDS, but the relapse rate (50 percent) was unacceptably high. Side effects include hepatitis (abnormalities of liver function) and interference with production of the male hormone testosterone.
Amphotericin B (Fungizone) has been used successfully in treating patients infected with various serious fungal diseases and has also been somewhat effective in preventing recurrences. Amphotericin B has several drawbacks, however. It must be given intravenously, and serious side effects are quite common. These include high fever, shaking chills, headache, nausea, loss of appetite, muscle and joint pain, suppression of blood-producing cells in the bone marrow, loss of serum potassium, and abnormal kidney function. Cardiac problems and changes in blood pressure may also occur. Persons taking the drug must be carefully monitored and may have to discontinue treatment because of the side effects. Amphotericin B is sometimes administered with oral flucytosine (Ancobon) for initial therapy of cryptococcal meningitis. Flucytosine can cause a significant decrease in the number of white blood cells and can also cause rash, nausea, diarrhea, and abdominal discomfort.
Fluconazole, another antifungal drug, has recently been approved for treatment of several fungal diseases, including cryptococcal meningitis and severe candidiasis. In a study sponsored by NIAID and the drug manufacturer, investigators found that fluconazole was as effective as or superior to amphotericin B in preventing recurrences of cryptococcal meningitis in AIDS patients who had been treated with amphotericin B for the acute phase of the disease. Another study showed that fluconazole can be used to treat acute cryptococcal meningitis. The advantages of fluconazole are that it can be taken by mouth or intravenously and does not require an acid environment for absorption. The most frequent side effects observed in trials of fluconazole have been rash, nausea, and hepatitis.
Itraconazole, a drug now being studied, appears to be more effective than ketoconazole against various fungal organisms,including Histoplasma. The drug appears to be tolerated well; side effects may include nausea, headache, fatigue, abdominal cramps, rash, loss of potassium, and edema (excess fluid in skin and subcutaneous tissue). In preliminary studies, itraconazole has not shown any adverse effects on testosterone.
SCH 39304 is another new antifungal drug that has shown activity against a wide range of systemic fungal infections in animal studies. It can be taken orally and has been shown to penetrate the central nervous system.
SCOPE OF THE NIAID EFFORT
The NIAID research effort to develop new therapeutic approaches for HIV-related OIs ranges from preclinical studies to clinical investigations in HIV-infected persons. NIAID has also given a high priority to basic research on the various organisms that cause opportunistic infections associated with HIV. Through its grant program, NIAID has established several new National Cooperative Drug Discovery Groups (NCDDGs), specifically to identify and develop treatments for HIV-related opportunistic infections. Like NIAID's existing NCDDGs that focus on anti-HIV therapies, each NCDDG-OI consists of a multidisciplinary team with the skills needed to design, synthesize, and evaluate, at the preclinical level, potential therapeutic agents for the treatment of HIV-related OIs, including fungal diseases.
NIAID conducts a number of clinical studies designed to evaluate agents for the prevention and treatment of several serious opportunistic infections, including fungal infections. These studies are being conducted by the AIDS Clinical Trials Group (ACTG) and the Mycoses Study Group (MSG) at sites located at academic research centers throughout the country.
NIAID supports the following clinical studies through the AIDS Clinical Trials Group (ACTG) and the Mycoses Study Group (MSG) to evaluate drugs for the treatment and prevention of fungal diseases in persons with HIV infection.
o A study of fluconazole compared with amphotericin B as maintenance therapy for the prevention of relapse of AIDS- associated cryptococcal meningitis (MSG trial and ACTG 026). The published results of this study showed that fluconazole at a dose of 200 mg per day is at least as effective, and possibly more effective, and is less toxic than amphotericin B in preventing relapse of cryptococcal meningitis in patients with AIDS.
o A comparison of fluconazole and amphotericin B as treatment for acute cryptococcal meningitis (ACTG 050 and MSG trial). This study is closed to enrollment and its data are being analyzed.
o Studies of itraconazole to treat acute histoplasmosis (ACTG 120) and prevent its recurrence (ACTG 084, 120).
o Study of SCH 39304 to treat acute cryptococcal meningitis and prevent its recurrence (MSG trial and ACTG 125). This trial is closed to enrollment and its data are being analyzed.
o Comparison of fluconazole and clotrimazole for the prevention of serious fungal diseases in persons with low T4 cell counts (less than 200 per cubic millimeter) who are receiving AZT and preventive therapy for Pneumocystis carinii pneumonia (ACTG 981).
MSG studies on fungal infections include the following (these studies accept persons with or without AIDS):
o Study of fluconazole in persons with coccidioidal meningitis.
o A dose-finding study of SCH 39304 for the treatment of progressive forms of coccidioidomycosis.
Information about ACTG studies may be obtained by calling 1-800-TRIALS-A.