A Phase I, placebo-controlled trial of multi-dose recombinant human interleukin-12 in patients with HIV infection.

OBJECTIVES

Interleukin (IL)-12 is a cytokine that stimulates T lymphocytes and natural killer cells to generate a Type 1 T-helper lymphocyte immune response. The primary objective of this study was to determine the safety and immunologic activity of repeated recombinant human IL-12 (rhIL-12) dosing in HIV-infected patients over a broad range of the HIV disease spectrum.

DESIGN

A randomized, placebo-controlled, Phase 1 trial design was chosen to control for the effects of HIV disease alone on safety and immunologic measurements.

METHODS

HIV-infected patients on antiretroviral therapy received rhIL-12 or placebo twice weekly for 4 weeks. Subjects were monitored for safety and changes in absolute lymphocyte subset number, serum interferon (IFN)gamma and neopterin levels, plasma HIV RNA level, peripheral blood mononuclear cell (PBMC)-inducible IFNgamma responses to mitogen, and PBMC proliferative responses to phytohemagglutinin, tetanus, Candida, Mycobacterium avium complex, streptokinase, and HIV p24 and gp160 antigens.

RESULTS

rhIL-12 was well tolerated at doses up to 100 ng/kg in subjects enrolled with CD4 cell counts < 50 x 10(6) cells/l and at all doses in subjects with CD4 cell counts of 300 x 10(6)-500 x 10(6) cells/l. rhIL-12 resulted in dose-related increases in serum neopterin (particularly in subjects with baseline CD4 cell counts of 300-500 x 10(6) cells/l) but in no significant changes in other immunologic measurements or plasma HIV RNA levels.

CONCLUSIONS

rhIL-12 dosed twice weekly at < or = 100 ng/kg was well tolerated in HIV-infected patients and resulted in dose-related increases in serum neopterin (possibly reflecting the effect of some degree of IFNgamma induction). However, there was no evidence of improvement in antigen-specific immune response.