The goal of this project is to conduct translational research aimed at developing improved and novel therapies for children with HIV infection and HIV-associated malignancies. In terms of HIV infection, both antiretroviral and immunologic approaches are currently being investigated. One focus during the past year has been to continue to evaluate in Phase I/II trials the highly active protease inhibitors indinavir and ritonavir. These drugs have been found to make a major impact on the care of adults with HIV infection, but until very recently have not been studied or available for children with HIV infection. These studies helped define the pharmacokinetics, toxicity, and activity of ritonavir and indinavir in children. Based in part on short term data from one of these trials, ritonavir was approved by the FDA for pediatric use in March 1997. Data generated from our phase I study of indinavir will be also be utilized to seek FDA approval for pediatric patients. We are currently studying the long-term virological and immunological effects of therapy with these agents and in particular their ability to effect immune reconstitution. We are also investigating two novel immunomodulatory agents in HIV-infected children: recombinant IL-2 and HIV-1 immunogen vaccine. Preliminary results from the latter have suggested that high dose immunogen vaccine administration is associated with a decrease in the viral load. In addition to delineation of toxicity and antiviral activities, an intensive focus is directed toward assessment of quantitative and qualitative measures of immune function associated with these therapies. We have also initiated a study of the novel antiretroviral agent F-ddA (lodenosine) in children. This agent, which was developed by the NCI, has been found to have little cross-reactivity to other dideoxynucleoside reverse transcriptase inhibitors and to even retain activity in strains of HIV with a Q151M mutation that has resistance to multiple dideoxynucleosides. We have also recently initiated studies of the immunoreconstitution achieved with a combination regimen of highly active antiretroviral therapy (HAART) and of the combination of ddI (didanosine) and hydroxyurea, stavudine, and efavirenz as a protease- sparing salvage regimen. In collaboration with members of the Pediatric Oncology Branch, we are also conducting studies of interferon-alpha and all-trans-retinoic acid for the treatment of HIV associated lymphoproliferative disorder. Also, a study is being initiated of of human papilloma virus (HPV) infection in females with vertically acquired HIV infection. Longitudinal studies of neurocognitive function, brain imaging and immune measures in children receiving antiretroviral therapy are being conducted in addition to investigation of the pathophysiology of HIV encephalopathy. Psychosocial studies include investigation of correlates of psychosocial functioning and coping strategies in long term survivors and longitudinal examination of psychological disturbances in HIV-infected, school-aged children, and the effects of participating in the Starbright program in which they can communicate by computer with sick children in other hospitals around the country. HIV/AIDS-related work accounted for 100% of this project; of this, about 15% is cancer-related. - AIDS, HIV, immune response, interleukin-2, pharmacokinetics, protease inhibitors, reverse transcriptase inhibitors, vaccines, neuropsychological, psychosocial, - Human Subjects: Minor under 18 Years Old
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