Opportunistic Infections Research-National Institute of Allergy and Infectious Diseases
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.
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.
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 March 1991