Hydroxyurea in combination with didanosine and stavudine in antiretroviral-experienced HIV-infected subjects with a review of the literature.

The safety and efficacy of hydroxyurea with didanosine in combination with stavudine in nucleoside reverse-transcriptase inhibitor (NRTI)-experienced patients was investigated. Entry criteria included HIV-1 infected, NRTI-experienced adults, with CD4(+) counts 50-550 cells/mm(3) and viral loads >or=12,500 copies/mL. Subjects were treated with didanosine 200 mg twice a day (BID), stavudine 40 mg BID, and hydroxyurea 1000 mg daily for 16 weeks. Thirty-one HIV-1 subjects with mean bDNA viral load 1x10(5) log(10) copies/mL and mean CD4(+) T-cell counts of 231 cells/mm(3) were enrolled. A 1.3 log(10) decrease in mean viral load was seen at 12 weeks of therapy. Prior didanosine use resulted in a more rapid response to therapy compared with prior zidovudine use. Side effects consisting of neutropenia, pancreatitis, and peripheral neuropathy occurred in four subjects and resolved upon withdrawal of therapy. This non-randomized study in subjects with a mean CD4(+) T-cell count of 230 cells/mm(3) demonstrates the antiviral activity of hydroxyurea+didanosine and stavudine. Toxicities related to therapy need to be followed closely. The results support the need for a randomized, prospective study to determine the safety and efficacy of hydroxyurea plus didanosine in antiretroviral-experienced patients with CD4(+) cell counts below 300 cells/mm(3).

Kinetics of tumor necrosis factor alpha and soluble TNFRII in HIV-infected patients treated with a triple combination of stavudine, didanosine, and hydroxyurea.

TNF-alpha is involved in the pathogenesis of HIV, and is known to enhance HIV replication in vitro. In this report the kinetics of plasma TNF-alpha and sTNFRII in patients receiving aggressive antiretroviral therapy and their relationship to HIV plasma RNA and CD4 cell counts were examined. Eleven patients participating in an open label study for assessment of safety, and of virological and immunological effects of simultaneous treatment with d4T, ddI, and HU, were evaluated. The CD4 cell count of the patients before treatment ranged from 65 to 374/mm3 and their HIV plasma RNA ranged from 1.9 x 10(4) to 3.7 x 10(5) copies/ml. The viral load in eight patients decreased significantly (mean, 1.9 log10). TNF-alpha and sTNFRII plasma levels pretreatment and at 8 weeks into therapy directly correlated with HIV plasma RNA. Pretreatment circulating TNF-alpha levels of 25-114 pg/ml (mean, 56 pg/ml) decreased by more than twofold in seven patients. The change in TNF-alpha levels inversely correlated with the change in absolute CD4 cell number. Detailed kinetics of TNF-alpha and sTNFRII measured at weeks 0, 1, 2, 4, 6, 8, and 12 paralleled those of HIV plasma RNA. A rapid decline in these soluble markers was always observed at week 1 together with the HIV plasma RNA response. Three patients maintained a high viral load as well as high TNF-alpha and sTNFRII. These data suggest that (1) combination therapy with d4T, ddI, and HU decreased viral load and circulating levels of TNF-alpha/sTNFRII; (2) an association exists between the TNF-alpha/sTNFRII and HIV viral load; and (3) TNF-alpha/sTNFRII might be a useful surrogate marker for predicting efficacy of antiretroviral therapy.

Dynamics and longevity of the glycolipid-anchored membrane protein, Thy-1.

Thy-1 and a number of other proteins are anchored to the outer hemi-leaflet of membranes by a glycolipid moiety containing ethanolamine phosphate, mannose, glucosamine, and phosphatidylinositol. They nevertheless have the striking property of being able to transduce signals across the plasma membrane. We here demonstrate, for the BW5147 murine T lymphoma, that (a) greater than 90% of Thy-1 is at the cell surface, (b) Thy-1 is about one order of magnitude less concentrated in coated pits than the transferrin receptor or H-2 antigens, (c) Thy-1 undergoes at most very limited endocytosis or diacytosis, and (d) Thy-1 has an unusually slow turnover rate. Several similar observations have also been made for a second glycolipid-anchored protein, the T cell activating protein. Thus, the absence of cytoplasmic and trans-membrane domains may result in lipid-anchored proteins being confined to the cell surface and being free from constraints which affect the turnover of transmembrane proteins.