This project addresses the major infectious complications of marrow transplantation, including cytomegalovirus (CMV), varicella-zoster virus (VZV) and fungal infections, primarily Candida. Studies addressing CMV include prevention of recurrent CMV infection with ganciclovir, phase 1 trials of a human monoclonal antibody with neutralizing activity against CMV (with subsequent efficacy trials to be proposed), and a randomized trial of filtered versus serologically screened blood products for prevention of primary CMV infection among seronegative patients. An orally administered prodrug of acyclovir will be tested for treatment of VZV infection. Clinical trials directed at fungal infection include a controlled trial of the new triazole antifungal agent fluconazole for prevention of yeast infection, and phase 1 (and subsequent efficacy trials) of a lipid-complexed formulation of amphotericin B for treatment of serious fungal infection. Studies of the biology and pathogenesis of Candida infection include: 1) determination of the prevalence of Candida albicans serotypes A and B in marrow transplant patients with colonization or infection compared with normal controls, 2) sensitivity testing of serotype B compared with serotyped A strains, and of Candida strains isolated from patients receiving fluconazole prophylaxis, 3) determination of adherence characteristics of isolates from patients with and without invasive infection in an ex vivo assay using tissues from a variety of immune compromised and immune competent mice and primates, and 4) correlation of serotype with adherence characteristics. Finally, a series of studies will further explore the ability to transplant patients with human immunodeficiency virus (HIV) infection initially using zidovudine, and later other agents including dideoxyinosine and soluble CD4, alone and in combination. The goal is to eradicate or suppress HIV infection to allow reconstitution of a functioning immune system, so that marrow transplant can be used successfully to treat HIV infected patients who have an underlying malignancy, or ultimately to treat HIV infection itself.
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