Combination Therapy with Recombinant Human Soluble CD4-Immunoglobulin G and Zidovudine in Patients with HIV Infection: A Phase I Study.

Meng, Tze-Chiang; Fischl, Margaret A.; Cheeseman, Sarah H.; Spector, Stephen A.; Resnick, Lionel; Boota, Ahmad; Petrakis, Tina; Wright, Brian; Richman, Douglas D.
Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology:

Summary: To determine the effect of zidovudine (ZDV) on the pharmacokinetic disposition of recombinant soluble CD4 immunoglobulin G (rCD4-IgG) and to evaluate the safety and preliminary activity of concurrent administration of ZDV with rCD4-IgG, we undertook an open-label, dose-escalating, 12-week study. The regimens of intravenous rCD4-IgG and oral ZDV we used were (a) 300 [mu]g/kg rCD4-IgG twice per week and 300 mg ZDV per day, (b) 300 [mu]g/kg rCD4-IgG twice per week and 600 mg ZDV per day, (c) 1,000 [mu]g/kg rCD4-IgG twice per week and 300 mg ZDV per day, (d) 1,000 [mu]g/kg rCD4-IgG twice per week and 600 mg ZDV per day, and (e) 3,000 [mu]g/kg rCD4-IgG twice per week and 300 mg ZDV per day. Subjects were recruited from three AIDS clinical trials units. Forty-one patients with HIV infection who had CD4 cell counts <=500 cells/mm3 and <=120 days of previous ZDV therapy participated. Pharmacokinetic interactions were assessed with the second regimen. Mean calculated peak serum rCD4-IgG concentrations were 5.47 [mu]g/ml with ZDV and 8.28 [mu]g/ml without ZDV, with serum half-lives of 34.2 and 32.0 h, respectively. Antibodies to rCD4-IgG were not detected. Seven episodes of severe adverse events occurred in five patients: one episode each of severe nausea, fever, or abnormal liver function tests and four episodes of severe neutropenia. Mean hemoglobin and neutrophil counts decreased, and mean platelet counts increased in all regimens, but there were no significant differences among regimens, rCD4-IgG dose, or ZDV dose. Mean CD4 cell counts rose with all regimens except the first, and mean serum p24 antigen declined with all regimens; however, there were no significant differences in CD4 cell count or serum p24 antigen response among regimens, ZDV doses, rCD4-IgG doses, or by previous ZDV therapy. CD4 lymphocyte elevations were neither greater nor more sustained than has been observed with ZDV alone. Combining ZDV with rCD4-IgG was well tolerated and did not appear to affect the pharmacokinetic disposition of rCD4-IgG. The response of surrogate markers did not appear to improve over that observed with ZDV alone.

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