Important note: Information in this article was accurate in 1988. The state of the art may have changed since the publication date.
PRELIMINARY RESULTS ON THE USE OF DIDEOXYNUCLEOSIDES IN THE THERAPY OF AIDS
Vaccines 87. Modern Approaches to New Vaccines: Prevention of AIDS and Other Viral, Bacterial, and Parasitic Diseases. Chanock RM et al, eds. New York, Cold Spring Harbor Laboratory, p. 214-24, 1987.. Unique Identifier : AIDSLINE ICDB/88647981 Yarchoan R; Broder S; Clinical Oncology Program, Div. of Cancer Treatment, NCI,; Bethesda, MD 20892
Abstract:
The discovery of human T-cell lymphotropic virus type III (HTLV-III) as the cause of acquired immune deficiency syndrome (AIDS) permitted consideration of therapy directed against the causative viral agent. The most striking clinical feature in AIDS is the development of a variety of unusual opportunistic infections as a result of a profound depression of the immune system, particularly a depression of cellular immunity in parallel with a fall in the number of CD4i helper-inducer T cells. Certain nucleoside analogs in which the 2'- and 3'-hydroxy groups are replaced by hydrogen or by other groups (dideoxynucleosides) are effective inhibitors of HTLV-III replication. These compounds become phosphorylated to a 5'-triphosphate form by cellular enzymes. Dideoxynucleoside triphosphates are selective inhibitors of reverse transcription; however, they inhibit DNA polymerases beta and gamma, and this inhibition may result in some toxicity, particularly after long-term administration. A dideoxynucleoside 3'-azido-3'-deoxythymidine (AZT), which was found to inhibit the infectivity and cytopathic effect of HTLV-III at concentrations of approx 1-3 uM, has already been studied in a Phase I trial, conducted by the NCI in collaboration with Duke University Medical Center, the University of Miami, and the Wellcome Research Foundation. The primary purposes of this Phase I trial were to test the feasibility of AZT administration to patients (pts) with HTLV-III infection and to determine the maximal tolerated dose and dose-limiting toxicities. Results of the Phase I study demonstrate that AZT can be safely administered to pts with HTLV-III infection for up to 12 mo, with the primary toxicity being bone marrow suppression. In addition, the results strongly suggest that AZT can induce at least short-term immunologic and clinical improvements in these pts. In three of four pts with neurological dysfunction attributable to HTLV-III infection, decreased neurologic symptomatology was observed while they were on AZT. The improvement was evident within the first 8 wk of therapy. AZT effectively penetrates the blood-brain barrier, and these results suggest that at least a subset of pts with HTLV-III-induced neurological disease can improve upon being administered AZT; the neurological manifestations of HTLV-III infection might thus have a reversible component. (25 Refs)
Keywords: Acquired Immunodeficiency Syndrome/*DRUG THERAPY Antiviral Agents/*THERAPEUTIC USE Drug Evaluation Human Structure-Activity Relationship Thymidine/*ANALOGS & DERIVATIVES/THERAPEUTIC USE MEETING PAPER
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Important note: Information in this article was accurate in 1988. The state of the art may have changed since the publication date.
