Immunomodulation induced by tucaresol in HIV infection: results of a 16 week pilot Phase I/II trial

Objective: Immune reconstitution in highly active antiretroviral 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/mu l, HIV RNA < 80 copies/ml; group B (n = 6): HAART-naive, CD4+ < 500 cells/ mu l, HIV RNA > 10000 copies/ml; group C (n = 3): HAART-naive, CD4+ > 500 cells/ mu l, HIV RNA < 10000copies/ml; and group D (n = 6): HAART, CD4+ < 200cells/mu l, HIV RNA < 80copies/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+ IFN gamma- 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.