AEGiS-NIAID: OPPORTUNISTIC INFECTIONS (Part 1): Pneumocystis Carinii Pneumonia, CMV Retinitis, AIDS-Related Fungal Illnesses, AIDS-Related Disseminated Histoplasmosis

Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.

OPPORTUNISTIC INFECTIONS (Part 1): Pneumocystis Carinii Pneumonia, CMV Retinitis, AIDS-Related Fungal Illnesses, AIDS-Related Disseminated Histoplasmosis

National Institute of Allergy and Infectious Diseases; - May 1991

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, AIDS has been diagnosed in more than 150,000 persons, and more than 100,000 deaths have been attributed to it. The leading cause of death in people with AIDS is Pneumocystis carinii pneumonia (PCP), one of a number of opportunistic infections (OIs) that attack individuals who have damaged or defective immune systems.

People infected with human immunodeficiency virus (HIV), the virus that causes AIDS, often have no symptoms for years. The eventual destruction of the immune system by HIV makes them particularly susceptible to the development of OIs, including a variety of viral, fungal, bacterial, and protozoal disease. Some of the infections associated with HIV are caused by microorganisms that may have been present in the body for a long time before infection with HIV. In persons who have normally functioning immune systems, the body is able to ward off or overcome reactivation of these infections. In persons with AIDS, however, infections caused by these organisms can become active and even life-threatening. AZT (zidovudine, Retrovir), the only drug approved to treat HIV, can delay the onset of these infections but does not prevent them. Consequently, safe and effective methods are needed to prevent and treat OIs in people infected with HIV.

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 PCP and other OIs.

NATURE OF THE DISEASE

PCP is the most common and often the first opportunistic infection to appear in people infected with HIV and is one of the illnesses used to establish the diagnosis of AIDS. PCP is caused by Pneumocystis carinii, a microscopic parasite that is thought to infect most humans during childhood. The organism normally remains dormant, but may cause disease in persons with damaged immune systems. The development of PCP is commonly associated with reduced numbers of lymphocytes or white blood cells known as CD+4 or T4 "helper" cells, critical components of the body's immune system, which are destroyed by HIV. Adults with HIV infection have a high risk of developing PCP if their T4 cells drop from a normal count of 1,000 to 200 cells per cubic millimeter or fewer.

PCP is typically characterized by a dry cough and shortness of breath. Individuals may, however, experience other, less specific, symptoms such as fever, fatigue, and weight loss for weeks or even months before respiratory problems appear. As PCP progresses to its most advanced form, the functioning lung tissue becomes clogged. This decreases the transport of oxygen from inhaled air into the blood, and blood oxygen may be lowered to dangerous or fatal levels.

MAGNITUDE OF THE PROBLEM

PCP is the most commonly recognized life-threatening manifestation of HIV infection in North America, Western Europe, and Australia. The disease occurs one or more times in about 85 percent of AIDS patients in these areas. According to current estimates, without prophylaxis (preventive treatment), more than 60,000 HIV-infected persons in the United States will have new or recurrent PCP infections in 1992.

Approximately 80 to 95 percent of adult AIDS patients receiving standard PCP treatment survive an initial attack of PCP, depending on the severity of the episode. After recovery most persons can return to their normal daily activities; however, recurrences of the disease are common unless preventive treatment is begun.

PCP exacts a high toll from the health care system: the average cost of treatment and care for a single individual hospitalized for PCP is estimated to be approximately $15,000. This cost varies according to the severity of illness, the occurrence of complications, and the geographic location of the health care facility. In addition, shortages of hospital beds and health care personnel can be exacerbated by the heavy PCP patient loads in some cities.

CURRENT THERAPIES

Since the early 1980s, management of PCP has been increasingly successful, and several effective therapeutic regimens are currently available. The standard therapy for an initial episode of PCP in HIV-infected persons is either a combination of trimethoprim and sulfamethoxazole (TMP/SMX, also called Bactrim or Septra) or pentamidine. Because of side effects, standard treatments for PCP must be discontinued in 30 to 50 percent of all cases, and even when treatment is successful, PCP commonly recurs in AIDS patients. Research has thus been directed towards the development of less toxic drugs to both treat and prevent PCP.

TMP/SMX has been effective in treating patients with PCP and in preventing recurrences. In patients with moderately severe cases of PCP, TMP/SMX is given intravenously and requires hospitalization. TMP/SMX can be given orally to individuals with mild cases of PCP or when patients improve sufficiently to be discharged from the hospital. TMP/SMX treatment, however, is frequently associated with toxic side effects and often is not tolerated for an entire course of therapy. The major side effects are skin rashes and lowered white blood cell counts; other adverse reactions include fever, nausea, vomiting and hepatitis (liver inflammation).

Pentamidine has been available in injectable form for treatment of PCP since 1984. Although this drug is effective against PCP, the injectable form is associated with severe side effects, including kidney failure, low blood sugar, low blood pressure, lowered white blood cell counts, and inflammation of the pancreas. Pentamidine also has been used to prevent PCP, in both injectable and inhalable (aerosol mist) form.

NEW THERAPEUTIC APPROACHES

In response to the toxicity problems and treatment failures associated with standard forms of therapy, extensive research has been undertaken to develop new approaches. The following drugs for PCP are in use or in clinical trials conducted or supported by NIAID:

o Aerosolized pentamidine o A combination of dapsone and trimethoprim o Trimetrexate o A combination of clindamycin and primaquine o BW566C80 o Corticosteroids (in addition to standard therapy) for moderate-to-severe episodes of PCP.

A promising form of preventive therapy involves using pentamidine in aerosolized form, so that the drug is delivered directly to the lungs, the primary site of most Pneumocystis infections. Pentamidine, diluted with sterile water, is inhaled by mouth using a nebulizer. As very little of the drug is absorbed from the lungs into the bloodstream, the adverse effects associated with injected pentamidine occur much less frequently. Common side effects include wheezing, cough, and fatigue during inhalation.

Another new approach uses a combination of oral dapsone and oral trimethoprim. In a limited clinical trial, this treatment has been found to be as effective as TMP/SMX in treating PCP, but with milder side effects. This combination has become popular because it can be given orally on an outpatient basis, may be tolerated better than oral TMP/SMX, and can be given to patients with allergies to TMP/SMX.

Trimetrexate, another experimental drug, is available to physicians under a Treatment IND as "salvage" therapy for individuals with PCP who cannot tolerate or do not respond to standard therapies. Trimetrexate must be given intravenously. Because it can be very toxic to the blood-producing cells of the bone marrow, it must be given in combination with leucovorin (folinic acid), a vitamin that protects human cells from trimetrexate.

The combination of intravenous or oral clindamycin and oral primaquine is also under investigation. This treatment appears to be effective and well tolerated by most patients. Although rash is a common side effect, it rarely requires termination of treatment.

BW566C80 is a new oral therapy for PCP that has an entirely different mechanism of action against Pneumocystis carinii from the previously described agents. It originally was developed as a treatment for malaria and in early stages of testing appears effective and well tolerated.

The addition of corticosteriods early in the course of specific therapy directed against Pneumocystis reduces the likelihood of deterioration of blood oxygen level, respiratory failure, and death in patients with moderate-to-severe episodes of PCP. Corticosteriods, such as oral prednisone or intravenous methylprednisolone, are most effective when started no later than 72 hours after beginning specific anti-Pneumocystis therapy. The recommended use of these steroids produces few side effects.

PREVENTIVE THERAPY

Aerosolized pentamidine (AP) prophylaxis received Food and Drug Administration approval in June 1989 as a result of a clinical trial comparing the value of different doses of AP in preventing PCP. The NIAID convened a consensus panel that reviewed available data in the winter of 1989. The panel's recommendations were published in June 1989 by the Centers for Disease Control. The U.S. Public Health Service adopted the panel's recommendation that preventive treatment with TMP/SMX or AP be given to HIV-infected persons who have significant deterioration of the immune system (T4 cell counts of 200 cells per cubic millimeter or lower) and in all individuals, regardless of T4 count, who have already had an episode of PCP. (Prior to the AIDS epidemic, TMP/SMX had been used successfully to prevent PCP in persons with cancer. Specific approval had never been sought from FDA, however, for TMP/SMX to prevent PCP in persons with AIDS.)

In addition to comparing the risks and benefits of TMP/SMX and AP in persons who have already had an episode of PCP, these two treatments and a third drug, dapsone, are being compared for the prevention of PCP in high-risk (T4 count less than 200/mm) individuals in two large ongoing studies of almost 1,200 participants.

SCOPE OF THE NIAID EFFORT

One of NIAID's primary goals is to develop new, less toxic, more effective therapeutic approaches for HIV-related OIs. The NIAID research effort ranges from preclinical research to clinical investigation in HIV-infected persons. NIAID has given a high priority to basic research for finding better agents to treat infectious diseases associated with HIV. NIAID has established several new National Cooperative Drug Discovery Groups (NCDDGs) specifically to identify and develop treatments for HIV-related OIs. Like the NCDDGs that focus on 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.

NIAID conducts a number of clinical studies designed to evaluate agents for the prevention and treatment of PCP as well as several other serious opportunistic infections. Some of these studies are being conducted by NIAID's AIDS Clinical Trials Group (ACTG) at sites located at academic research centers throughout the country, and by NIAID's Community Program for Clinical Research on AIDS (CPCRA) at community treatment centers. In addition, NIAID scientists are conducting PCP studies at the Clinical Center of the National Institutes of Health (NIH) in Bethesda, Maryland.

The discovery of treatments for PCP that are less toxic, more potent, and easier to administer than current therapies is expected to increase the life expectancy and improve the quality of life for HIV-infected persons, decrease the frequency of adverse side effects, and produce significant savings in both human and medical costs.

CLINICAL STUDIES

NIAID supports the following ACTG studies for PCP. NIAID supports the following ACTG studies for PCP. Unless otherwise noted, these studies are ongoing:

* Comparison of aerosolized pentamidine and oral trimethoprim/sulfamethoxazole to prevent the recurrence of PCP in patients who have had at least one episode (ACTG 021). This study is fully enrolled and is now in the followup phase.

* Studies of aerosolized pentamidine (ACTG 040), clindamycin plus primaquine (ACTG 044, 108), and dapsone plus trimethoprim (ACTG 108) for patients suffering from active PCP. ACTG 040 is closed to enrollment and its data are being analyzed; ACTG 044 is a completed pilot study; and ACTG 108 will begin during 1991.

* Comparison of aerosolized pentamidine, oral trimethoprim/sulfamethoxazole, and oral dapsone as preventive therapy in patients who have never had PCP but are at high risk because of low T4 cell counts (less than 200 cells per cubic millimeter) (ACTG 081). Nested within this PCP prophylaxis study is a comparison of oral fluconazole and oral clotrimazole for the prevention of serious fungal diseases (ACTG 981). ACTG 081 is fully enrolled and is now in the followup phase.

* Comparison of BW566C80 and oral trimethoprim/sulfamethoxazole for the treatment of mild to moderate PCP (ACTG 167). This study also is being conducted at the NIH Clinical Center.

Studies conducted by NIAID and other intramural NIH investigators at the NIH Clinical Center focus on the following:

* Oral piritrexim (a drug to trimetrexate) and leucovorin for treatment of HIV-infected persons with active PCP who have not received treatment for the current episode. This study is completed and its data are being analyzed.

* Evaluation of dapsone versus dapsone/pyrimethamine as prophylaxis for PCP in persons who have had PCP in the past or are at risk because of low T4 cell counts.

* Evaluation of the safety and efficacy of an oral investigational drug, BW566C80, in the treatment of mild-to- moderate Pneumocystis pneumonia in persons infected with HIV.

* A comparison study of BW566C80 versus TMP/SMX (Septra) for treatment of mild-to-moderate PCP in HIV-infected patients.

* A study of dapsone versus dapsone plus pyrimethamine for the prevention of PCP in HIV-infected patients.

Information about ACTG and intramural studies may be obtained by calling 1-800-TRIALS-A.

March 1991

BACKGROUNDER

Opportunistic Infections Research - National Institute of Allergy and Infectious Diseases

CMV RETINITIS

Acquired immunodeficiency syndrome (AIDS), a life-threatening infectious 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.

People infected with HIV often have no symptoms for years, but the eventual destruction of the immune system by the virus makes these persons particularly susceptible to the development of opportunistic infections (OIs), which include a variety of viral, fungal, bacterial, and parasitic diseases. AZT (also called zidovudine or Retrovir), the only drug approved to treat HIV infection, can delay the onset of these infections but does not prevent them. Consequently, safe and effective methods are needed to prevent and treat OIs in persons infected with HIV.

One of the more common and serious infections associated with AIDS is cytomegalovirus (CMV) retinitis, a viral infection of the retina, the structure at the back of the eye that sends images to the brain. CMV retinitis affects approximately 10 to 25 percent of persons in the late stages of AIDS. If untreated, CMV retinitis causes blindness in the affected eye or eyes.

NATURE OF THE DISEASE

CMV retinitis is caused by a virus in the herpes family. An estimated 80 percent of Americans are infected with CMV, but the infection usually does not result in illness except in persons who have damaged immune systems. CMV infections can occur in the gastrointestinal tract, lungs, and other organs. Retinitis is the most frequent CMV infection in persons with AIDS.

The first sign of CMV retinitis may be blurred vision, "floaters"- dark specks that drift down through the field of vision, or the loss of peripheral vision in one or both eyes; however, the lesions are often "silent" or undetected until the areas of the retina essential for vision are involved. An eye examination will reveal characteristic retinal lesions regardless of whether the individual has begun to have symptoms. Whereas identification of CMV virus in blood or urine confirms the diagnosis, an experienced ophthalmologist (eye doctor) can reliably diagnose this infection by examination. Occasionally, the ophthalmologist makes the diagnosis during a routine screening examination before symptoms develop. Progression (enlargement of a lesion or development of a new one) typically occurs within 2 to 3 weeks in the absence of effective treatment.

Before AIDS, CMV retinitis was so rare that an ophthalmologist might not see even one case in a lifetime of clinical practice. Currently, the frequency of AIDS-associated CMV retinitis is estimated at 8 to 30 percent of total AIDS patients during their expected lifetime. Usually, CMV retinitis is a complication of advanced HIV disease and occurs in persons with CD4+ (T4 "helper") cell counts of less than 50 cells per cubic millimeter, attacking individuals who already have AIDS. Less commonly, it may be the AIDS-defining illness.

CURRENT THERAPIES

Two drugs, foscarnet and ganciclovir, have been shown to delay the progression of CMV retinitis in persons with AIDS. The recommended procedure for ganciclovir treatment consists of full intravenous doses twice daily for 2 weeks, followed by daily maintenance therapy with a reduced dose. Because ganciclovir does not kill CMV but merely slows down its ability to grow, lifelong maintenance therapy is required to control the disease. CMV retinitis significantly improves or initially stabilizes in approximately 70 to 90 percent of patients who receive the initial course of therapy. However, over an extended period of time, many patients will experience progression despite daily maintenance therapy.

For several years, ganciclovir was available only for compassionate use to treat CMV retinitis and other CMV infections. In June 1989, the Food and Drug Administration (FDA) approved intravenous ganciclovir for treatment of CMV retinitis.

The most serious side effect of ganciclovir is suppression of the blood-producing cells of the bone marrow, resulting, primarily, in a reduction in the number of white (infection-fighting) blood cells and less commonly, a reduction in platelets,which are essential for blood clotting. More than one-third of the persons taking ganciclovir have low white blood cell (WBC) counts by the end of induction therapy, and more than half develop this problem some time during maintenance therapy. In some persons the WBC count becomes so low that they must discontinue ganciclovir therapy until their WBC count recovers. The intermittent nature of this therapy appears to contribute to an increased rate of relapse.

Ganciclovir's effect on bone marrow cells is a particular problem in persons with HIV infection who may already have low WBC counts because of their HIV infection itself. In addition, AZT which is being taken by increasing numbers of persons with HIV infection, also suppresses bone marrow cells. AZT and ganciclovir frequently cannot be taken together because they can produce profound depression of WBC counts. An additional drawback of ganciclovir is the potential for development of resistance to the drug in some patients.

Another experimental method of administration for persons who cannot tolerate ganciclovir for a long time because of side effects may be to inject very small amounts of ganciclovir directly into the eye (intravitreally) rather than intravenously. Because the absorption of ganciclovir from the eye into the bloodstream is negligible, it is possible that patients will not experience the severe side effects associated with intravenous administration.

Other Therapeutic Approaches

Because ganciclovir does not cure CMV retinitis and so many people either cannot take the drug or must discontinue therapy due to low WBC counts, alternative therapies are essential. Foscarnet appears to be a promising alternative at this time, and clinical trials to find the best intravenous dose level are underway. This drug does not appear to affect white blood cell counts, although it has been associated with low red blood cell counts (anemia). Foscarnet may have detrimental, though reversible, effects on kidney function and on the level of calcium in the blood. Patients taking foscarnet may also take AZT because depression of WBC counts associated with AZT is not worsened by foscarnet and anemia can be treated with transfusions or erythropoietin therapy.

High-dose acyclovir in combination with AZT is also under study. Although acyclovir alone is not effective against active CMV infection, it may be useful in preventing CMV disease or in preventing recurrence of the illness after initial induction therapy with ganciclovir.

Two oral forms of treatment are in early phases of clinical trials. Ganciclovir in pill form can reach concentrations in blood that inhibit most strains of CMV even though it has limited absorption from the gut. The other oral drug is FIAC/FIAU.

SCOPE OF THE NIAID EFFORT

NIAID has established several National Cooperative Drug Discovery Groups (NCDDGs) specifically to identify and develop treatments for HIV-related opportunistic infections. Like the NCDDGs that focus on 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 CMV retinitis.

NIAID conducts a number of clinical studies designed to evaluate agents for the prevention and treatment of several serious infections, including agents for the treatment of CMV retinitis and for its subsequent suppression. Studies are being conducted by the AIDS Clinical Trials Group (ACTG) at sites located at academic research centers throughout the country and at the Clinical Center, National Institutes of Health (NIH), Bethesda, Maryland.

CLINICAL STUDIES

NIAID supports the following studies of CMV infection:

* Study of high-dose intravenous acyclovir and oral AZT to prevent recurrence of CMV retinitis in patients previously treated with ganciclovir (ACTG 070). This study is closed to enrollment and its data are being analyzed.

* Comparison of immediate and deferred treatment with ganciclovir in persons in whom CMV retinitis is not sight- threatening (ACTG 071). This study has been closed because of poor enrollment.

* Comparison of ganciclovir alone and with granulocyte- macrophage colony stimulating factor (GM-CSF) to determine whether the addition of GM-CSF is useful in preventing low WBC count, which is a side effect of ganciclovir. This addition might enhance the effectiveness of ganciclovir by eliminating or minimizing interruptions of therapy (ACTG 073).

* Study of intravitreal ganciclovir (injected into the eye) in patients with active CMV retinitis who cannot tolerate systemic (intravenous) ganciclovir therapy (ACTG 085).

* Study of foscarnet therapy for patients with sight- threatening CMV retinitis who cannot be treated with ganciclovir because of low WBC counts or because of treatment failure (ACTG 093). This study is closed to enrollment and its data are being analyzed.

* A study of the safety and effectiveness of FIAC/FIAU given orally to AIDS patients with CMV infection (ACTG 122).

* Study of the effectiveness of ganciclovir given orally for the treatment of CMV retinitis and CMV infection of other organs (ACTG 127).

* Comparison of ganciclovir and foscarnet for previously untreated CMV retinitis (ACTG 129). This study is a collaborative effort of NIAID and the National Eye Institute and is also known as Study of the Ocular Complications of AIDS (SOCA).

* Pilot study of combination therapy with ganciclovir and foscarnet as "suppressive" or maintenance therapy for AIDS patients who have completed the initial course of ganciclovir therapy (ACTG 151).This study will open in 1991.

* A study of foscarnet in persons in whom CMV retinitis is not sight-threatening and who have not been treated previously for the disease (conducted at the Clinical Center, NIH).

Information about ACTG studies may be obtained by calling 1-800-Trials-A.

BACKGROUNDER

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.

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.

CURRENT THERAPIES

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.

CLINICAL STUDIES

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.

* 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.

* 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.

* Studies of itraconazole to treat acute histoplasmosis (ACTG 120) and prevent its recurrence (ACTG 084, 120).

* 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.

* 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):

* Study of fluconazole in persons with coccidioidal meningitis.

* 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. March 1991

BACKGROUNDER

Opportunistic Infections Research-National Institute of Allergy and Infectious Diseases

AIDS-RELATED DISSEMINATED HISTOPLASMOSIS

Acquired immunodeficiency syndrome (AIDS), a life-threatening disease of the immune system, has become a worldwide epidemic since 1981, the year AIDS was first identified as a disease. In the United States alone, AIDS has been diagnosed in more than 150,000 persons, and more than 100,000 deaths have been attributed to it.

The fungal organism that causes histoplasmosis in HIV-infected individuals may have been present in the body for a long time. It rarely causes disease in persons who are protected by normally functioning immune systems. When the immune system is damaged by HIV, the infections can become active, causing serious or life-threatening disease. Even persons taking AZT (zidovudine, Retrovir, the only approved anti-HIV drug, are not protected from histoplasmosis and other OIs. Consequently, safe and effective methods are needed to prevent and treat OIs in persons infected with HIV.

NATURE OF THE DISEASE

Histoplasmosis is a common infection in certain regions of the world, such as the midwestern United States and the Caribbean. Persons who have ever lived or traveled in such areas can acquire histoplasmosis by inhaling or ingesting spores of the fungus Histoplasma capsulatum. The disease begins as an acute pneumonia or influenza-like illness, and then disseminates to other organs, including the meninges (covering of the brain and spinal cord), heart, peritoneum (lining of the abdominal wall), and adrenal glands.

Approximately 5 to 10 percent of persons with HIV infection who live in areas where Histoplasma capsulatum is found develop disseminated histoplasmosis. The illness also occurs in persons with AIDS who now live outside these areas but resided there in the past. Histoplasmosis can be a serious, life-threatening illness for persons with AIDS.

CURRENT THERAPIES

Persons with histoplasmosis usually respond initially to the standard therapy, intravenous amphotericin B (Fungizone). Unfortunately, the infection recurs in 80 to 90 percent of these persons, often within 1 year, unless suppressive (maintenance) treatment is continued beyond the initial course of therapy. The treatment itself, however, commonly causes serious side effects. These include high fever, shaking chills, headache, nausea, loss of appetite, muscle and joint pain, suppression of the blood-forming cells of the bone marrow, depletion of serum potassium, and abnormal kidney function. Cardiac problems and changes in blood pressure can also occur. Individuals taking amphotericin B must, therefore, be carefully monitored and may have to discontinue treatment because of these adverse effects.

Other Therapeutic Approaches

Because amphotericin B has so many serious side effects, less toxic, more effective therapies are essential. Ketoconazole, a drug that can be taken by mouth, has demonstrated some activity against other fungal diseases. In preliminary studies, however, only a few persons with AIDS who had active histoplasmosis responded to this drug. Ketoconazole has been used with some success to prevent recurrence of the disease, but 50 percent of those given this drug still relapsed while on medication. This may be due in part to the fact that the drug is inadequately absorbed in AIDS patients because their secretion of stomach acid is impaired. Serious side effects of ketoconazole include abnormalities of liver function and interference synthesis of the male hormone testosterone.

Itraconazole, a related drug currently under study, appears to be more effective against various fungal organisms. Furthermore, this drug appears to be tolerated well. Nausea, headache, fatigue, abdominal cramps, rash, depletion of serum potassium, and edema (retention of excess fluid in the body tissue) are among its relatively uncommon side effects observed so far. Unlike ketoconazole, itraconazole has thus far not shown any effects on male hormone production.

SCOPE OF THE NIAID EFFORT

One of the primary goals of NIAID is the development of new therapeutic approaches for HIV-related OIs. The NIAID research effort ranges from preclinical study to clinical investigation in HIV-infected persons. NIAID has given a high priority to basic research for finding better ways to treat infectious diseases associated with HIV. NIAID has established severa National Cooperative Drug Discovery Groups (NCDDGs) specifically to identify and develop treatments for HIV-related opportunitic infections. Like the 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 disseminated histoplasmosis.

NIAID is conducting a number of clinical studies designed to evaluate agents for the prevention and treatment of several serious infections, including agents for the prevention, treatment, and subsequent suppression of disseminated histoplasmosis. Most of the studies are being conducted by the AIDS Clinical Trials Group (ACTG) at sites located at academic esearch centers throughout the country. Clinical trials of anti-fungal drugs are also conducted by NIAID's Mycoses Study Group (MSG), a nationwide network of medical centers devoted to research on serious fungal diseases.

CLINICAL STUDIES

NIAID-sponsored studies include the following ACTG and MSG trials:

* Study of itraconazole maintenance therapy to prevent recurrence of disseminated histoplasmosis in patients previously treated with amphotericin B (ACTG 084).

* Study of itraconazole for treatment of acute disseminated histoplasmosis and for subsequent maintenance therapy (ACTG 120).

* Comparison of fluconazole and clotrimazole to prevent serious fungal diseases, including disseminated histoplasmosis, in persons with low T4 cell counts (less than 200 cells per cubic millimeter) who are receiving AZT and preventive therapy for Pneumocystis carinii pneumonia (ACTG 981).

Information about ACTG studies may be obtained by calling 1-800-TRIALS-A.

Keywords: PCP, CMV retinitis, Opportunistic infections, Fungal illnesses, Disseminated histoplasmosis. ACTG.
910510
NI910501

Published 1991 - National Institute of Allergy and Infectious Diseases . All material contained in this report is in the public domain and may be used and reprinted without special permission; citation to source, however, is appreciated.

AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, Elton John AIDS Foundation, iMetrikus, Inc., John M. Lloyd Foundation, the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2003. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980, 2003. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content. .