Immunomodulation Induced by Tucaresol in HIV Infection: Results of a 16 Week Pilot Phase I/II Trial

Abstract

Objective

Immune reconstitution in highly active anti-retroviral therapy (HAART)-treated individuals is incomplete and immunomodulatory compounds are needed to improve the outcome of HIV therapy. In a Phase I/II clinical trial performed on HIV-positive patients we analysed the safety and immunomodulating effects of tucaresol, a novel compound that has previously been described to enhance cell-mediated immune responses.

Patients and methods

Sixteen weeks pulse dose escalation protocol. Four groups of HIV-positive patients were enrolled: group A (n=6): HAART, CD4+ 300–500 cells/μl, HIV RNA <80 copies/ml; group B (n=6): HAART-naive, CD4+ <500 cells/μl, HIV RNA >10 000 copies/ml; group C (n=3): HAART-naive, CD4+ >500 cells/μl, HIV RNA <10 000 copies/ml; and group D (n=6): HAART, CD4+ <200 cells/μl, HIV RNA <80 copies/ml. Tucaresol was added to HAART in group A and D patients; group B patients started tucaresol with HAART, group C patients received tucaresol alone. Clinical and immunological analyses were performed at different time points.

Results

Tucaresol-related serious adverse events were observed in the first week of therapy in 2/21 patients who were viraemic when commencing treatment, but did not occur in patients on stable HAART. Tucaresol did not affect HIV viraemia whereas increases in CD4+ percentages, mainly supported by naive CD4+ cells, were observed. CD8+/28-/45RA+ cells and HIV-specific CD8+ IFNγ- and perforin-producing cells improved whereas IL-10 mRNA diminished in tucaresol-treated patients. The effects were greater with 25 mg given every other day for 1 week.

Conclusion

In HAART-receiving patients with proper virus suppression, tucaresol was not associated with serious adverse events and resulted in qualitative and quantitative stimulation of HIV-specific cytotoxic T lymphocyte activity and generation of naive T cells. These data may support further exploration of tucaresol use in reconstitution of immune system parameters in HIV patients with proper virus suppression while on HAART.