PHASE I II TRIAL OF THE TYPE-I SOLUBLE RECOMBINANT HUMAN INTERLEUKIN-1 RECEPTOR IN HIV-1-INFECTED PATIENTS/

Interleukin-1 (IL-1) produced in peripheral blood mononuclear cell (PB MC) cultures or added exogenously has been shown to upregulate HIV exp ression in vitro. Inhibition of IL-1 in HIV-infected individuals may i nhibit HIV activation and slow disease progression, Recombinant human IL-1 receptor (rHu-IL-1R), the soluble extracellular portion of the hu man type I IL-1 receptor, inhibits HIV expression in acutely infected primary PBMCs and in the chronically infected promonocytic cell line, U1. We, therefore, conducted a phase I/II trial of the soluble rHu-IL- 1R in HIV-1-infected individuals with CD4 T cell counts <300/mu l to e valuate its safety and activity. Twelve evaluable patients were enroll ed at three rHu-IL-1R dose levels:125 (n = 3), 500 (n = 3), and 1250 ( n = 6) mu g/m(2) per dose by subcutaneous (s.c.) injection three times a week for 8 weeks, followed by a 4 week observation period, rHu-IL-1 R was safe and well tolerated. There were no deaths, no treatment-rela ted grade 3/4 events, and no premature study discontinuations because of adverse events. The maximum tolerated dose was not reached, Seven p atients reported improvements in one or more symptoms, including weigh t gain (3), improved energy level (4), decreased diarrhea (1), decreas ed night sweats (1), improvement in psoriatic arthritis (1), and impro vement in a nonspecific chronic diffuse skin rash (1), Of 3 evaluable patients with Kaposi's sarcoma, 1 remained stable and 2 showed minimal progression, No consistent trends in absolute CD4 counts or percentag es, quantitative HIV cultures, or serum p24 antigen, beta(2)-microglob ulin, or triglyceride levels were observed, rHu-IL-1R is safe and well tolerated at the doses tested but induced no consistent changes in ob jective markers of HIV disease, Symptomatic improvements will require confirmation in randomized, placebo-controlled trials.