Background: HIV-associated immune defects are incompletely restored by HAART. The effect of tucaresol, a Schiff-base forming immunomodulant, was analyzed in different stages of HIV infection.

Methods: Phase I/II increasing pulse dose study (25 mg qd/week to 100 mg 4 times/wk). Four groups were enrolled: A (n = 6): stable HAART, CD4 300-500/mL, VL < 80 cp/ml; B (n = 6) HAART-naive, CD4 < 500/mL, VL > 10,000 cp/ml; C (n = 3): HAART-naive, CD4 > 500/mL, VL < 10,000 cp/ml; D: (n = 6) stable HAART, CD4 < 200/mL, VL < 80 cp/mL. A and D patients (pts) added tucaresol to HAART; B pts started HAART together with tucaresol; C pts started tucaresol without HAART. Tucaresol was used for 13 wks; 40 wks of follow-up were evaluated. Wilcoxon Signed Rank Tests were used.

Results: Tucaresol-related serious adverse events (SAE) were seen in 2/21 pts, were observed in the first week of therapy, were not dose-dependent and did not occur in pts on stable HAART. ELISpot g-IFN, env- and p24- stimulated CD8 cells increased in all groups reaching statistical significance in A and D patients (p < 0.05) but returned to baseline at wk 16, with the exception of group D who maintained a significant increase at wk 24 (p < 0.05). In parallel, intracellular perforins increased in all groups (overall analysis wks 5 and 9: p < 0.05) returning to baseline at week 16. IL-10-specific m-RNA decreased in all groups maintaining significance in group A (p < 0.05) and in the overall analysis (p < 0.01) at wk 24; all pts increased IL-12 and IL-2-specific m-RNA (IL-12 overall analysis at wk 12: p < 0.05 and IL-2 at wk 24: p ≤ 0.05). Naïve CD4 increases (p ≤ 0.001 for group A and for the overall analysis) were observed during tucaresol administration and persistently maintained in all the groups (p < 0.005 at wk 40 for group B and D). CD8/28-/45RA cells (effectors) increased in all the pts with statistical significance in group D (p < 0.05) and in the overall analysis (p < 0.01). The tendency to increase persisted also at the follow-up with statistical significance in group B and in the overall analysis (p ≤ 0.005).

Conclusions: Tucaresol pulse dosing resulted in qualitative and quantitative stimulation of HIV-specific CTL activity and generation of naïve T=cells. Maintenance of these effects at wk 40 of follow-up warrants further exploration of tucaresol use in reconstitution of immune system parameters in HIV pts treated with HAART.