Therapeutics
Therapeutics research includes drug discovery and development as well as clinical trials.
Research progress in comprehensive drug screening and rational (targeted) drug-design programs includes screening of more than 210,000 natural and synthetic agents to date for anti-HIV activity, describing the structural and functional characteristics of viral gene products to guide drug discovery efforts, and supporting the basic biomedical research that resulted in developing the protease inhibitor class of drugs.
Research progress at networks of more than 250 clinical trial sites includes determining that multidrug combination therapy benefits patients, determining that AZT given to pregnant women and their babies reduces perinatal transmission by two-thirds, and defining standards of care for treatment and prevention of several HIV-associated opportunistic infections.
Treatment identified to improve the quality of life of HIV-infected persons includes nutritional supplements to minimize wasting; dietary changes to help control diarrhea; and interventions to improve fatigue and endurance.
The clinical testing of drugs against HIV, HIV-associated OIs and malignancies, and CNS dysfunctions requires an active preclinical drug discovery and development program. The NIH supports two major approaches in the area of drug development, including screening and rational (targeted) drug programs. The screening approach involves the testing of natural and synthetic compounds for anti-HIV activity. Rational (targeted) drug development involves characterization and delineation of the structural biology of HIV and its components for the purpose of developing agents targeted at inhibiting specific steps in the HIV life cycle.
The preclinical AIDS Drug Screening Program has approved six new drugs for Phase I clinical studies. Approximately 218,000 agents have been screened for anti-HIV activity to date through this program. A new panel of cell lines has been developed for testing agents for activity against HIV-related malignancies. Five hundred agents have been tested in the new lymphoma subpanel, and eight of these agents that demonstrated activity are being tested further in the SCID mouse model for efficacy compared with other antilymphoma agents.
NIH-sponsored, investigator-initiated research supports drug discovery efforts. Basic biomedical research on HIV pathogenesis provides crucial information relevant for drug discovery and development efforts. The NIAID-sponsored National Cooperative Drug Discovery Groups (NCDDGs) and the National Cooperative Drug Discovery Groups for the Treatment of the Opportunistic Infections Associated with AIDS (NCDDG-OIs) have expanded collaborative efforts with academia, industry, and government researchers for targeted drug discovery and development of potential treatments for HIV infection and HIV-associated OIs. The NIAID-sponsored Mycoses Study Group tests agents for improved microbial therapy of systemic mycotic diseases. New standards of care have resulted from these studies. The NIGMS Targeted Antiviral Program provides extramural investigators with access to sophisticated techniques, while a similar program has been established for NIH intramural scientists through the Intramural AIDS Targeted Antiviral Program.
These combined programs have resulted in the discovery and/or development of AZT, ddI, ddC, d4T, recombinant soluble CD4, atovaquone, rifabutin in combination with atovaquone, ofloxacin, paromomycin, tat inhibitors, protease inhibitors, and compounds that attack the zinc (Zn) finger and the nucleocapsid. The first generation of protease inhibitors has been approved by the FDA.
Program projects and associated R01s organized to develop approaches to structure-based targeted drug design have resulted in progress in determining the structure of several HIV components, such as integrase, RNaseH, p24, reverse transcriptase, and the Zn fingers of the nucleocapsid. Potential inhibitors of these compounds for the treatment of HIV infection and AIDS are currently being tested. New approaches for the development of HIV protease inhibitors also are under way. Although the newly developed drugs show initial promise, the development of resistance over a relatively short period of time may limit the effectiveness of single drug regimens. The use of these drugs in combination is currently being tested to overcome problems of drug resistance.
Scientists also are exploring novel molecular strategies to slow or halt HIV replication in vivo. One such strategy will test uniquely designed constructs of defective HIV proviral DNA that will target cells expressing HIV envelope protein, in order to interfere with viral replication. This type of antiviral therapy would down regulate viral replication and reduce viral load, thus potentially delaying progression to AIDS. The NIAID-supported Strategic Program for Innovative Research on AIDS Treatment Strategies (SPIRATS) fosters coordinated and interdependent basic and clinical research between state-of-the-art studies in HIV pathobiology and clinical evaluation of novel therapeutic strategies.
In order to further decrease HIV transmission, there is a need to develop innovative strategies to incorporate effective behavior change strategies into clinical studies and therapeutic guidelines.
The development of therapeutic regimens to block HIV infection or delay disease progression while maintaining quality of life is the major goal of these efforts. Ongoing preclinical and clinical efforts are testing agents, individually and in combination, to block the viral life cycle and the pathogenic processes resulting from infection. These programs also are evaluating approaches to restore immune function and/or reverse immunologic dysfunction in infected individuals.
The NIH, through its intramural and extramural programs, has developed a multifaceted approach to the discovery, development, and preclinical and clinical evaluation of anti-OI agents. Priority is placed on the identification of effective strategies where established therapies do not exist and on the evaluation of new agents with the potential for improving efficacy or reducing toxic effects of existing treatment or prophylactic regimens. OIs represent the most common cause of morbidity and mortality of HIV-infected individuals. Evaluation of anti-OI strategies is a priority within the NIAID-funded AIDS Clinical Trials Group (ACTG) and Community Programs for Clinical Research on AIDS (CPCRA). Approximately 50 percent of the NIAID-sponsored Mycoses Study Group (MSG) studies and trials are targeted to HIV-related fungal infections.
Biomedical research on OIs is challenged by the limited understanding of the basic biology and natural history of the causative micro-organisms; the lack of in vitro culture systems for susceptibility testing and biochemical studies; the lack of targeted screens or rational design of new agents; the need for optimization of animal models for testing treatment and prophylactic regimens; the need for evaluation of drug combinations for efficacy and safety, drug interactions, pharmacology, and immunotoxicology; and the relatively low level of interest shown by pharmaceutical manufacturers in the development of agents against HIV-associated OIs.
Goals of specific preclinical and clinical projects planned for each of the OIs are as follows:
The NCI AIDS Lymphoma Network is pursuing innovative therapies for AIDS-related lymphomas including monoclonal antibody conjugates, cytotoxic chemotherapy with antiretroviral agents, hematopoietic simulators, and biologic response modifiers. Collaboration between NCI Clinical Cooperative Groups and the NIAID ACTG will further enhance clinical trials of potential agents against AIDS-related cancers. The Task Force on AIDS Malignancies has been established to coordinate cross-ICD clinical trial efforts in this area.
The NIH has the primary responsibility for the federally supported clinical trial efforts in the evaluation of potential therapies for the treatment of HIV infection and its sequelae. These efforts consist of 35 adult AIDS Clinical Trials Units (ACTUs) and 22 Pediatric ACTUs supported by the NIAID- funded AIDS Clinical Trials Group (ACTG), 16 NIAID-funded Terry Beirn Community Programs for Clinical Research on AIDS (CPCRAs), 50 sites of the NIAID-sponsored Division of AIDS Treatment Research Initiative (DATRI), 27 NICHD-funded sites that are full partners in the Pediatric ACTG, 12 NEI-funded sites, and 3 NIH intramural sites. More than 45,000 patients have been enrolled to date in NIH-sponsored clinical studies, which have involved the evaluation of nearly 80 agents.
Accomplishments in NIH-sponsored clinical trials include demonstration of the efficacy and clinical benefits of AZT for both adults and children with early and asymptomatic infection; the safety and efficacy of ddI and ddC for HIV-infected adults and children; the benefits of ddI and ddC in patients who are intolerant of or who have failed AZT treatment; the antiviral activity of interferon and its benefits for reducing Kaposi's sarcoma lesions; the utility of paclitaxel in advanced KS; the benefits of nimodipine for the treatment of AIDS dementia complex; and the therapeutic benefits of ddC plus AZT combination therapy with FDA approval of the regimen.
A NIAID- and NICHD-sponsored clinical trial has demonstrated that AZT administered during gestation and labor and to the infant after birth reduces the rate of HIV transmission by approximately 67 percent. Accomplishments of NIH-sponsored clinical trials in the past year include the completion of two combination nucleoside trials in the adult and one in the pediatric HIV-infected populations which demonstrated clinical superiority of ddI monotherapy and ddI/ZDV combination therapy over ZDV monotherapy; other NIH-sponsored trials have shown clinical benefit of treatment of oral aphthous ulcers with Thalidomide, recombinant human growth hormone for treatment of AIDS-associated Wasting Syndrome (AWS), and megestrol acetate for AWS. Additional NIH trials have contributed to the further understanding of the use of protease inhibitors, such as Saquinavir, Indinavir, and Ritonavir, nucleoside analogs, such as d4T and 3TC, and nonnucleoside reverse transcriptase inhibitors, such as nevirapine and delavirdine, and the impact of these agents on viral load and on clinical outcomes. In the further understanding of HIV pathogenesis, studies have been undertaken involving the use of potent agents to explore the viral cycle, viral turnover, and CD4 turnover, as well as a study investigating the development of mutations predictive of resistance.
As administration of therapeutic agents occurs only during periods of organ system development in the growing child, evaluating potential late toxic effects is an important component of therapeutic research in infected children. Such effects may not be observed with therapy in adults who have fully developed organ systems.
Accomplishments in combating HIV-associated OIs include demonstration of the efficacy of TMP-SMX, atovaquone (566C80), dapsone, and aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia (PCP) in patients intolerant of TMP-SMX; TMP-SMX for prophylaxis of recurrent PCP; aerosolized pentamidine for prophylaxis and treatment of PCP; fluconazole for the treatment of cryptococcal meningitis and prevention of fungal infections; foscarnet for the treatment of CMV retinitis; IV gamma globulin for reducing OIs in HIV-infected children with CD4+ counts greater than 200/mm3; the combination of pyrimethamine and clindamycin for toxoplasmic encephalitis; and itraconazole for disseminated histoplasmosis (shown to be more effective with fewer side effects than amphotericin B).
The unique mode of HIV transmission from mother to infant constitutes a major difference between adult and pediatric HIV infection. Interventions to prevent transmission are of high priority, and intervention trials should elucidate important pathogenic factors associated with vertical transmission that apply to other transmission modes. It is especially important to identify the reasons for treatment failures. These intervention trials include evaluating long-term followup of infants (both uninfected and infected) exposed to antiretroviral agents in utero for late toxicity. The trials also include evaluating infected women who received prophylactic treatment during pregnancy following treatment discontinuation. There are significant differences between the manifestations of HIV infection in children and those in adults. Also, the pharmacokinetics, toxicity, and beneficial response profiles of therapeutic agents are often a function of age due to tissue/organ immaturity, requiring specific evaluation of potential agents in children of different ages.
Specific preclinical and clinical projects involving HIV-infected pediatric patients will seek to:
It is critical that the participation of specific populations in NIH-funded clinical trials reflect the changing demographics of HIV infection and AIDS, including women, children, adolescents, drug abusers, IDUs, minorities, the urban poor, and individuals residing in rural areas. Recruitment and enrollment of these underrepresented populations is a high priority in NIH-sponsored studies and should be a consideration within each objective of this section. Whenever possible, interagency collaboration should be fostered to enhance participation of these populations, including provision of ancillary services.
The NIH has published and implemented new and strengthened guidelines for the inclusion of women and minorities in clinical trials.
The NIAID-supported clinical trials programs (ACTG, CPCRA, DATRI) strive to ensure that a sufficient proportion of minority participants are enrolled into the clinical trials so that the results of the research may be generalizable to the affected HIV population at large. NIAID works with these networks to identify the need for and/or assist in the development of culturally sensitive education materials, identify real or potential barriers to recruitment and retention in clinical research for these groups, and identify mechanisms to overcome these barriers.
Pediatric clinical trials enroll principally minority populations. The NIAID/NICHD funded collaborative PACTG enables the flexibility to adjust the location of trials sites to accommodate the changing epidemiology of HIV in women and children along with the establishment of advanced technology sites for investigators of pathogenesis in the context of clinical trials.
"The ACTG has also sought to increase the number of underrepresented participants in a proportion reflective of the spectrum of the infected population, including prioritizing gender-specific clinical trials in the overall scientific agenda."
In addition, the ACTG supports the AIDS Clinical Trials Infrastructures in Minority Institutions to enhance HIV clinical research performed at minority institutions. Four institutions, located at Howard University (Washington, DC), Meharry Medical College (Nashville, TN), the University of Puerto Rico (San Juan), and the University of Hawaii (Honolulu), received 4-year awards as adult ACTUs. This program increases the number of minority staff involved in ACTG research and the number of minority participants in the studies.
Drug-abusing populations are at risk for receiving intermittent or interrupted therapy. This should be considered in the development of therapeutics in terms of (1) developing delivery systems that minimize adherence demands, (2) understanding the implications of such interrupted treatment for each therapeutic regimen that is developed, (3) developing strategies for minimizing the undesirable effects of interrupted treatment, and (4) studying interactions between drugs of abuse and new anti-HIV and/or anti-OI pharmacotherapies in terms of alterations in pharmacokinetics, development of adverse consequences, or progression of disease.
For more information on Therapeutics HIV/AIDS-related research at the NIH, contact:
Robert Eisinger, Ph.D.
Office of AIDS Research, NIH
Building 31, Room 4B62
Bethesda, MD 20892
(301) 402-8655 TELEPHONE
(301) 402-8638 FAX
Last Update: October 8, 1996
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