National Institute of Allergy and Infectious Diseases OI Backgrounder - May 1991

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.

The most common life-threatening fungal infection seen in persons with AIDS is cryptococcal meningitis, an infection of the meninges-the membranes that surround the brain and spinal cord. When left untreated, cryptococcal meningitis is invariably fatal.

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 to prevent and treat cryptococcal meningitis and other OIs.

NATURE OF THE DISEASE

Cryptococcal disease accounts for about 5 to 8 percent of all the opportunistic infections in persons diagnosed with AIDS. Cryptococcal meningitis is caused by Cryptococcus neoformans, a yeast like fungus that is found widely in the environment, especially in soil contaminated with bird excrement. Although exposure to C. neoformans is quite common, disease rarely occurs except in persons who have damaged immune systems.

Cryptococcus can infect numerous organs-particularly the skin, lungs, and meninges. The most common form of cryptococcal infection in AIDS patients is meningitis. The first signs of cryptococcal meningitis may be vague and include fever, headache, fatigue, nausea, or vomiting. The infection may cause changes in behavior or personality, and possibly memory loss and confusion. Difficulty with coordination also may occur. Diagnosis of the disease is made by identification of the fungus or fungal antigen (protein) in the patient's cerebrospinal fluid. More than half of the patients with meningitis also have cryptococcal infection in other organs. Relapse after initial treatment occurs in 50 to 90 percent of persons with cryptococcal meningitis, unless lifelong maintenance (suppressive) therapy is initiated.

CURRENT THERAPIES

The standard therapy for acute cryptococcal meningitis has been daily intravenous administration of amphotericin B for about 10 weeks with or without oral flucytosine, another antifungal drug. The length of treatment depends on the response of the individual. It is not certain whether the addition of flucytosine improves the treatment in AIDS patients, as has been demonstrated in other populations, or whether it prevents relapse. Amphotericin B can have serious side effects. These include kidney damage, high fever, severe chills, low blood pressure, decreases in potassium levels in blood, and depressed levels of red and white blood cells and platelets. Flucytosine, which also suppresses the blood- forming cells of the bone marrow, can cause rash, nausea, diarrhea, and abdominal discomfort.

Fluconazole, another antifungal drug, was recently approved for treatment of several fungal diseases, including cryptococcal meningitis and severe candidiasis. An advantage of fluconazole is that it can be taken orally or intravenously and does not require an acid environment for absorption. In a study sponsored by NIAID's AIDS Clinical Trials Group, the Mycoses Study Group (MSG), and the drug manufacturer, investigators found that fluconazole is at least as effective and may be superior to amphotericin B in preventing recurrences of cryptococcal meningitis in AIDS patients who already had been treated successfully with amphotericin B for the acute phase of the disease. Another NIAID-sponsored study comparing fluconazole with amphotericin B for treatment of acute cryptococcal meningitis was one of the bases for FDA approval of fluconazole.

Other Therapeutic Approaches

NIAID is conducting research studies of experimental antifungal agents that can penetrate the central nervous system for both acute and maintenance therapy of cryptococcal meningitis in persons with AIDS.

An experimental drug, SCH 39304, is active against a wide variety of fungal infections, including those caused by Cryptococcus. This drug can be taken orally and penetrates the central nervous system. In laboratory studies, SCH 39304 is more potent than fluconazole and equal to amphotericin B in antifungal activity.

SCOPE OF THE NIH EFFORT

One of NIAID's primary goals is to develop 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 on the discovery and development of drugs to treat the infectious diseases associated with HIV. Through its grant program, NIAID supports several National Cooperative Drug Discovery Groups (NCDDGs) specifically to identify and develop treatments for HIV-related OIs. Like the existing 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 cryptococcal meningitis.

NIAID conducts a number of clinical studies designed to evaluate agents for the prevention and treatment of serious OIs, including agents for the treatment of cryptococcal meningitis and its subsequent suppression. These studies are being conducted by the AIDS Clinical Trials Group (ACTG) and the NIAID-sponsored Mycoses Study Group (MSG) at sites located at academic research centers throughout the country.

CLINICAL STUDIES

NIAID supports the following ACTG studies for cryptococcal meningitis:

* A study of fluconazole compared with amphotericin B as maintenance therapy for the prevention of relapse of AIDS- associated cryptococcal meningitis (ACTG 026). The published results of this study showed that fluconazole at a dose of 200 mg per day is at least as effective as and 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 059). This study is closed to enrollment and its data are being analyzed.

* A study of SCH 39304 as therapy for acute cryptococcal meningitis, followed by maintenance therapy (ACTG 125). This study is closed to further enrollment and its data are being analyzed.

* A comparison of fluconazole and clotrimazole for the prevention of serious fungal diseases, including cryptococcal meningitis, in persons with T4 cell counts less than 200 cells per cubic millimeter who are receiving AZT and preventive therapy for Pneumocystis carinii pneumonia (ACTG 981).

TOXOPLASMIC ENCEPHALITIS

Acquired immunodeficiency syndrome (AIDS) is an infectious disease of the immune system, which in the past 10 years has become a worldwide epidemic. In the United States alone, more than 150,000 persons have been diagnosed with AIDS since 1981, the year AIDS was first identified as a disease, and more than 100,000 deaths have been attributed to it.

The human immunodeficiency virus (HIV), the virus that causes AIDS, attacks the body's immune system. People infected with HIV often have no symptoms for years; however, the eventual destruction of the immune system by HIV makes these persons particularly susceptible to the development of opportunistic infections (OIs), including a variety of protozoal, viral, fungal, and bacterial diseases. Encephalitis (infection of the brain) caused by the protozoan parasite Toxoplasma gondii is the most frequently occurring central nervous systems infection in persons with AIDS.

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 because the body's immune system is damaged. AZT (zidovudine, Retrovir, the only drug approved to treat HIV, can delay the onset of OIs but does not protect the body against them. Consequently, safe and effective methods are needed that specifically 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 toxoplasmic encephalitis and other OIs.

NATURE OF THE DISEASE

Between 20 and 30 percent of all adults in the United States are infected with Toxoplasma gondii at some point during their lifetimes. The parasite can be passed to humans by contact with the feces of infected cats or transmitted in undercooked meat from other infected animals. Although most people manifest few or no symptoms of disease, the parasite never leaves the body and can be reactivated in persons with damaged or suppressed immune systems. Reactivation or new acquisition of Toxoplasma infection in such persons can result in encephalitis, a dangerous, life-threatening disease. In some persons infected with HIV, Toxoplasma infection (toxoplasmosis) causes inflammation of parts of the eye.

Toxoplasmic encephalitis symptoms vary from mild headache and fever to nervous system impairment, including neurologic problems, seizures, diminished alertness, and even coma. The most useful diagnostic tests for toxoplasmic encephalitis are specialized X-rays of the brain-computerized tomography (CT) or magnetic resonance imaging (MRI).

AIDS-associated toxoplasmosis exhibits sharp regional variations in occurrence: it is uncommon in the western United States but is frequently seen in the eastern and southern regions, particularly in cities with substantial immigrant populations from the Caribbean, such as New York and Miami. By the end of 1991, as many as 20,000 cases of toxoplasmic encephalitis will have been diagnosed in persons with HIV infection in the United States.

CURRENT THERAPY

For the past 25 years, the standard therapy for toxoplasmic encephalitis has been a combination of pyrimethamine and sulfadiazine.

In approximately 40 percent of persons with AIDS who receive pyrimethamine and sulfadiazine for toxoplasmic encephalitis, side effects are severe enough to require discontinuation of the treatment. The side effects include suppression of the blood-forming cells in the bone marrow (resulting in reduced red and white blood cells, and reduced number of platelets). Leucovorin (folinic acid) is given to minimize this side effect. Other reactions include occurrence of crystals and blood in the urine, fever, severe rashes, abdominal discomfort, headaches, and abnormalities in liver function. If treatment is discontinued, relapse usually occurs within days or weeks.

New Therapeutic Approaches

In response to the toxicity problems associated with standard therapy, research has been undertaken to develop new therapeutic approaches that are less toxic and more effective.

Preliminary studies suggest that clindamycin in combination with pyrimethamine is effective in treating toxoplasmic encephalitis. Diarrhea is the most common side effect associated with clindamycin. Inflammation of the large intestine (colitis) occurs in up to 10 percent of patients. Other significant side effects of clindamycin include rash, abnormalities in liver function, and abdominal discomfort.

The absorption and blood levels of pyrimethamine have varied widely in AIDS patients with encephalitis, so that research in pharmacokinetics (studies of how drugs act in the body) is warranted in order to improve treatment with this important agent.

Other new antibiotics under study, such as azithromycin, clarithromycin, and BW566C80, may play a role in the treatment and prevention of toxoplasmic encephalitis. These drugs are given by mouth and can be administered less frequently than either sulfadiazine or clindamycin.

Preventive Therapy

Clinical trials of drugs to prevent toxoplasmic encephalitis have begun recently in the United States. At the present time, no preventive regimen has been established. Although pyrimethamine and sulfadiazine, which have been effective in treating the disease, might also be effective in preventing toxoplasmic encephalitis, the severe side effects of long-term use are a problem. The trials are enrolling persons at high risk (those who have toxoplasma antibodies) and are testing pyrimethamine and clindamycin, a combination less likely to be toxic, for effectiveness in preventing encephalitis.

SCOPE OF THE NIAID EFFORT

One of the primary goals of the NIAID is the development of less toxic and more effective therapeutic approaches for HIV- related OIs. The NIAID research effort ranges from preclinical study to clinical investigation in HIV-infected persons. NIAID has also given priority to basic research for finding better ways to treat infectious diseases 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 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.

At the clinical level, NIAID is conducting studies designed to evaluate agents for the treatment of toxoplasmic encephalitis as well as a number of other serious OIs. Studies are being conducted throughout the country by NIAID's AIDS Clinical Trials Group (ACTG) at sites located at academic research centers and by the Community Programs for Clinical Research on AIDS (CPCRA), at NIAID-supported community-based research centers. In addition, NIAID scientists are conducting studies of some OIs at the Clinical Center of the National Institutes of Health (NIH) in Bethesda, Maryland.

CLINICAL STUDIES

Studies conducted by the ACTG include the following:

* Evaluation of the safety and efficacy of an oral combination of pyrimethamine, clindamycin, and leucovorin (folinic acid) in treating AIDS-related toxoplasmic encephalitis (ACTG 077P).

* A pharmacokinetic study of pyrimethamine to determine how the drug acts in the body (ACTG 102).

* A study comparing pyrimethamine to placebo is being conducted in collaboration with investigators in France, where toxoplasma infection is far more common (ACTG 154).

* A phase I/II pilot study of azithromycin for acute and long-term suppressive treatment (ACTG 156).

The CPCRA is conducting a community-based AIDS clinical trial:

* A study evaluating the effectiveness of pyrimethamine in preventing toxoplasmic encephalitis in HIV- infected individuals with latent Toxoplasma gondii infection.

Studies conducted by NIAID and NIH Clinical Center intramural scientists include the following:

* A pilot study of pyrimethamine and dapsone for the treatment of central nervous system toxoplasmosis in persons infected with HIV.

* A study of the safety and efficacy of BW566C80 in AIDS patients with toxoplasmosis who are intolerant or unresponsive to the standard therapy.

AIDS-RELATED HERPES SIMPLEX VIRUS INFECTION

Acquired immunodeficiency syndrome (AIDS), a life-threatening disease of the immune system, has become a worldwide epidemic since 1981,the year it was first recognized. 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 individuals 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. The eventual destruction of the immune system by HIV makes these persons particularly susceptible to the development of opportunistic infections (OIs), including a variety of viral, fungal, bacterial, and protozoal diseases. Herpes simple virus (HSV) infections in persons infected with HIV usually occur as a result of the reactivation of virus that has been present in the body long before infection with HIV. HSV causes skin and mucous membrane infections in persons with HIV infection, just as it does in individuals with normal immune systems. In persons with HIV, however, these reactivated infections may be severe and protracted. Longstanding severe HSV lesions, in fact, can be one of the first symptoms of AIDS. Nonetheless, even in AIDS patients, HSV lesions typically remain localized and do not spread throughout the body.

The National Institute of Allergy and Infectious Diseases (NIAID) has 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 to treat or prevent OIs, including HSV infections.

NATURE OF THE DISEASE

Two types of HSV can cause herpes or sores. HSV type 1 more commonly causes oral (on or near the mouth) herpes, also known as fever blisters or cold sores. Genital lesions are usually caused by HSV type 2 and may occur in the vaginal area, on the penis, around the anal opening, and on the buttocks or thighs. Occasionally, herpes lesions appear on other parts of the body that have come into direct contact with HSV type 1 or 2.

HSV infections in persons infected with HIV are common. The number of HSV infections that are resistant to the standard treatment appears to be increasing, and the resistant viruses can cause substantial local tissue destruction and discomfort.

CURRENT THERAPIES

Acyclovir, given by mouth or intravenously, provides both effective treatment and preventive therapy for HSV infections in persons with or without HIV infection. During recent years, however, there have been reports of HSV developing resistance to acyclovir. In persons with healthy immune systems, acyclovir resistance can be overcome by increasing the dose of the drug. Persons with damaged immune systems, such as those with HIV infection, are at increased risk of developing acyclovir-resistant HSV infections that will not heal despite maximal doses of drug. Because of the growing phenomenon of acyclovir resistance in persons with AIDS, alternative treatments are needed.

Other antiviral drugs are being tested for possible use in treating acyclovir-resistant HSV infections in persons with AIDS. Foscarnet, a drug that must be given intravenously, has been used with some success.

SCOPE OF THE NIH 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 also given a high priority to basic research for finding better agents to treat infectious diseases associated with HIV. NIAID has established several National Cooperative Drug Discovery Groups (NCDDGs), specifically to identify and develop treatments for HIV-related OIs. Like the 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 mucous membrane and skin HSV infections.

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 treatment of HSV infections. Studies are being conducted by the AIDS Clinical Trails Group (ACTG) and by the Collaborative Antiviral Study Group (CASG) at sites located at academic research centers throughout the country.

CLINICAL STUDY

NIAID supports the following study of HSV infection:

* Comparison of foscarnet and vidarabine for treatment of acyclovir-resistant HSV infections (ACTG 095). This study has been completed and its data are being analyzed.

AIDS-RELATED CRYPTOSPORIDIOSIS

Acquired immunodeficiency syndrome (AIDS) is an infectious disease of the immune system. Since its identification in 1981, AIDS has become a worldwide epidemic. 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 the disease.

People infected with HIV often have no symptoms for years. The eventual destruction of the immune system by HIV makes these persons particularly susceptible to the development of opportunistic infections (OIs), including a variety of protozoal, viral, fungal, and bacterial diseases. The most devastating gastrointestinal infection seen in persons with AIDS is severe diarrhea caused by the protozoan Cryptosporidium.

In persons who have normally functioning immune systems, the body is able to overcome infection with Cryptosporidium. In persons with AIDS, however, Cryptosporidium infection can be severe and even life-threatening because the body's immune system is damaged. Even persons taking AZT (zidovudine, Retrovir,) the only drug approved to treat HIV, are not protected. Consequently, safe and effective methods are needed to prevent and treat this OI 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 OIs, including Cryptosporidium-induced diarrhea.

NATURE OF THE DISEASE

Cryptosporidiosis is a major cause of diarrheal illness in humans worldwide. The parasite lives in cattle and domestic animals and is excreted in feces. It can be transmitted to humans from animals or via contact with feces, contaminated water, or food. In persons with normal immune systems, Cryptosporidium causes acute diarrhea with flu-like intestinal symptoms that go away after a week or more without treatment.

In persons with AIDS, cryptosporidiosis is a serious, debilitating illness. Along with chronic, watery, sometimes uncontrollable diarrhea, other symptoms include abdominal cramps, nausea, vomiting, fever, and headache. Weakness and weight loss often accompany bouts of the disease, which can persist for weeks or months. Fluid loss may be so massive as to be life-threatening. The infection can spread to other digestive organs such as the gallbladder, causing nausea, vomiting, and severe localized pain. A diagnosis of cryptosporidiosis is made by microscopic examination of stool specimens (treated with special stains) for the organism.

Approximately 50 percent of persons with AIDS in the United States suffer from some form of diarrhea, but only 4 percent are reported to have cryptosporidiosis at the time of their initial diagnosis of AIDS. The actual number of patients who develop cryptosporidiosis later in the course of their HIV infection is believed to be higher. Cryptosporidiosis is more common in AIDS patients in other countries.

CURRENT THERAPIES

A variety of agents have been used against cryptosporidiosis, but none have been effective. Supportive therapy with fluids and nutrients given orally or intravenously is used to treat severe illness.

In some people, cryptosporidial infections seem to respond to an oral form of spiramycin, an antibiotic similar to erythromycin. The oral from of the drug, however, is poorly absorbed, which may limit its effectiveness. A study of intravenous spiramycin has recently completed enrollment in NIAID's AIDS Clinical Trials Group (ACTG).

Other agents being tested against cryptosporidiosis in various medical centers include diclazuril, hyperimmune bovine colostrum, and a synthetic form of the hormone somatostatin. In some people, these treatments help control the diarrhea temporarily but do not eliminate the organism that causes the disease. The inability to grow this organism in the laboratory has limited clinical exploration of a broader range of agents.

No preventive treatment is yet available for diarrhea caused by Cryptosporidium. Careful handwashing after contact with potentially infected animals or humans offers the best protection against infection.

SCOPE OF THE NIAID EFFORT

One of the primary goals of the NIAID is the development of new therapeutic approaches for HIV-related OIs. The NIAID research effort ranges from preclinical study to clinical investigations in HIV-infected persons. NIAID has given a high priority to basic research for finding better ways to treat the infectious diseases associated with HIV. NIAID has established several 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, including cryptosporidiosis.

NIAID sponsors a number of clinical studies to evaluate agents for the prevention and treatments of AIDS-related infections, including cryptosporidiosis. NIAID studies are conducted by the ACTG at sites located at academic research centers throughout the country.

CLINICAL STUDY

NIAID sponsors the following ACTG trial:

* Evaluation of the safety and effectiveness of intravenous spiramycin in treating AIDS-related cryptosporidial diarrhea (ACTG 113). This study is closed to enrollment and its data are being analyzed.

HIV-ASSOCIATED OPPORTUNISTIC INFECTIONS: NIAID-SUPPORTED PRECLINICAL AND CLINICAL RESEARCH

The urgent need to develop effective treatments for opportunistic infections (OI) that take advantage of the weakened immune system will become even more pressing in the 1990s as thousands of asymptomatic HIV-infected people become ill.

The first cases of AIDS were brought to light by the observation of increasing frequencies of such illnesses as Pneumocystis carinii pneumonia (PCP) and ulcerative herpes among homosexual men. Since then, the range of HIV-associated OIs has continued to expand.

The National Institute of Allergy and Infectious Diseases (NIAID), under the leadership of its Director, Anthony S. Fauci, M.D., has designated the understanding and treatment of HIV-associated OIs as high-priority research areas. Currently, one-third of both the active clinical trials sponsored by NIAID's nationwide AIDS Clinical Trials Group (ACTG) as well as those conducted by NIAID intramural staff in Bethesda, Maryland, are evaluating agents to prevent and treat OIs.

Preclinical Research

The Developmental Therapeutics Branch (DTB), part of NIAID's Division of AIDS (DAIDS), coordinates the major share of NIAID-supported preclinical investigations of HIV-associated OIs. DTB serves as a national resource for any individual or group of scientists interested in developing drugs against such OIs.

Traditionally, most drugs for infectious diseases have been discovered through random drug screening. Random screening of drugs for anti-HIV activity continues under a National Cancer Institute program. DTB, on the other hand, focuses on a newer approach to finding anti-HIV and anti-OI agents. This approach is called targeted drug discovery: that is, learning as much about the microbe as possible, and designing drugs that home in on vulnerable targets of that microbe.

To facilitate the discovery and development of promising anti- OI agents, DTB has in place specific programs that foster collaborations between government, academic, and industry scientists. DTB staff coordinate a five-arm, structured OI program consisting of: (1) the National Cooperative Drug Discovery Groups for Opportunistic Infections; (2) investigator-initiated basic research grants; (3) contracts to identify agents active against opportunistic pathogens; (4) contracts to analyze the efficacy and toxicity of single and combination therapies in animal models; and (5) resources to conduct chemical formulation and synthesis studies. DTB staff work closely with the staff of the DAIDS Treatment Research Program (TRP) to ensure that the best anti-OI drugs reach the clinic quickly.

In addition to the DTB effort, a smaller effort focused on viral OIs is integrated into the longstanding program of the Antiviral Research Branch (ARB) of the Institute's Division of Microbiology and Infectious Diseases (DMID). ARB oversees programs of drug discovery and development and provides animal models of important viral diseases in which promising compounds can be tested.

In September 1989, the Institute brought together a diverse group of infectious disease experts to address future directions in OI research. This workshop, cosponsored by DAIDS and ARB, drew more than 150 investigators from university, government, and industry laboratories. Current knowledge about specific pathogens was discussed and a recommended strategy to accelerate the development of OI therapies was developed.

Buttressing the Institute's newer programs is its 42-year history of commitment to funding basic research on infectious organisms, including bacteria, viruses, fungi, and parasites. NIAID's strong support of immunology research complements this ongoing effort by illuminating how these pathogens destroy or disrupt the body's immune system to allow diseases to develop.

Clinical Research

The majority of NIAID-supported clinical OI research is carried out by ACTG investigators, who are funded through the TRP. The ACTG is a network of 47 university-based adult and pediatric AIDS clinical trials units around the country. The rapidity with which such a large-scale clinical trials effort was established is extraordinary in the history of modern medicine.

Through the ACTG, TRP staff, and the ACTG's Harvard-based Statistical and Data Analysis Center, NIAID provides national leadership on (1) fostering and conducting clinical research to identify optimal therapies for HIV disease and OIs, (2) broadly disseminating the results of this clinical research, and (3) facilitating the application of such results to medial practice. The ACTG's ability to perform large, multicenter trials has positioned it at the vanguard of the HIV clinical trials movement, with several advances in anti-HIV clinical research to its credit. In the area of OIs, the ACTG has also made major contributions to the prevention and treatment of PCP, cytomegalovirus (CMV) retinitis, histoplasmosis, and cryptococcal meningitis.

Clinical research on OIs is enhanced by the new Community Programs for Clinical Research on AIDS (CPCRA). DAIDS established CPCRA to involve more primary care practitioners in the clinical research effort and to reach large, traditionally underserved populations-blacks, Hispanics, women, and intravenous drug users. CPCRA investigators have identified treatment and prevention of OIs as their top priority.

The staff of NIAID's Division of Intramural Research conduct their own clinical investigation program at the National Institutes of Health's Clinical Center in Bethesda. Intramural investigators have performed several important OI clinical trials, particularly for PCP and CMV retinitis. They also continue to characterize the disease processes underlying OIs. They pioneered studies that have led to a greater understanding of PCP, especially the importance of T4 counts as an indicator of the population at risk for the disease. These data were used by the Food and Drug Administration (FDA) to define the population in which aerosolized pentamidine prophylaxis would be used when it first became licensed.

Intramural and extramural investigators supported by DMID also continue clinical research on infectious pathogens. Two special clinical programs contribute to this effort. The NIAID Collaborative Antiviral Study Group is a multicenter project of 55 clinical investigators focused on rare herpesvirus infections, such as herpes encephalitis. The Mycoses Study Group, cosponsored by DMID and DAIDS, is a similar nationwide network of 28 medical centers dedicated to clinical research on serious fungal diseases.

Staff heading all these NIAID programs work closely with the FDA and industrial drug sponsors in planning and executing the clinical trials. This close communication helps ensure that the most promising OI drugs are developed as quickly as possible and that the resultant data are both scientifically significant and acceptable to FDA for licensing purposes.

Prepared by: Office of Communications National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892

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.

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