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Immunological effects of human, immunodeficiency virus (HIV) protease inhibitor, ritonavir.
Kelleher A; Zaunders J; Carr A; Cooper D; Centre for Immunology, St.
December 30, 1996
Annu Conf Australas Soc HIV Med. 1995 Nov 16-19;7:53 (abstract no. 44).

We explored the immunological effects of a HIV protease inhibitor, Ritonavir, in patients enrolled in a multi-centre, randomised placebo-controlled double-blind phase I/II study. 11 subjects had detailed phenotypic analysis of changes in subsets of CD4+ and CD8+ T-cells by dual colour immunofluoresence flow cytometry. 9 of these subjects had T-cell proliferative responses to, phytohaemagglutinin (PHA), and to antigens, tetanus toxoid (TT), streptokinase/streptodornase (SK/SD) and HIV core proteins p24 and p17, studied over the first 20 weeks of active therapy. In 6 patients the capacity of lymphocytes to produce IL2 was studied using the CTLL-2 bioassay. 9 of 21 had remission of various HIV-related conditions. Significant increases in CD4+ and CD8+ lymphocyte counts and decreases in plasma HIV RNA levels were observed. These changes were sustained for at least 24 weeks in those receiving high dose therapy. Initial increases in total CD4+ count were associated with increases in CD4+CD45RO+ and CD4+CD28+ cells. Increases in CD4+CD45RA+ cells were noted after 4 weeks of therapy. A decrease in the proportion CD4+ and CD8+ cells marking with CD38 was noted. There was no reduction in expression of HLA-DR in either subset. In vitro improvements in T-cell function as determined by proliferative responses to PHA were seen in 8/9 subjects. Improvements in responses to recall antigens TT (2/9), SK/SD (6/9) and HIV specific antigens p24 and p17 (2/9) were observed. 4/6 patients had increased production of IL2 at 4 weeks. The duration of improved proliferative capacity correlated with the duration of viral load reduction (Rho = 0.84, P < .05). Ritonavir appears to be a promising agent for the treatment of HIV causing significant changes in surrogate markers, lymphocyte subsets and improvements in T-cell function. Further study of the effects of this drug on T-cell subsets and function may give insight into the immunopathogenesis of HIV/AIDS.

Antiviral Agents/*PHARMACOLOGY Double-Blind Method Human HIV Infections/*DRUG THERAPY/*IMMUNOLOGY HIV Protease Inhibitors/*PHARMACOLOGY In Vitro Interleukin-2/BIOSYNTHESIS Lymphocyte Count Lymphocyte Transformation T-Lymphocyte Subsets/DRUG EFFECTS/IMMUNOLOGY Thiazoles/*PHARMACOLOGY Valine/*ANALOGS & DERIVATIVES/PHARMACOLOGY ABSTRACT CLINICAL TRIAL CLINICAL TRIAL, PHASE I CLINICAL TRIAL, PHASE II MULTICENTER STUDY RANDOMIZED CONTROLLED TRIAL

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