L-CHICORIC ACID, AN INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) INTEGRASE, IMPROVES ON THE IN-VITRO ANTI-HIV-L EFFECT OF ZIDOVUDINE PLUS A PROTEASE INHIBITOR (AG1350)

Combinations of anti-human immunodeficiency virus (HIV) drugs, includi ng reverse transcriptase inhibitors and protease inhibitors, have prov en immensely potent in the therapy of acquired immune deficiency syndr ome (AIDS). To determine whether HIV integrase is a suitable target fo r combination therapy, the ability of an HIV integrase inhibitor, L-ch icoric acid, to work in combination with a protease inhibitor and Zido vudine was tested in vitro. The addition of L-chicoric acid to either Zidovudine or protease inhibitor improved upon the observed anti-HIV a ctivity of either compound alone. When all three drugs were combined, the anti-HIV activity was substantially better than either of the thre e compounds alone or any combination of two inhibitors. Doses of both Zidovudine and protease inhibitor could be reduced by more than 33% fo r an equivalent anti-HIV effect if L-chicoric acid was added. The impr oved anti-HIV activity was observed with a tissue culture adapted stra in of HIV (HIVLAI) and with limited passage clinical isolates of HIV ( HIVR19 and HIVR45). These data demonstrate that a first generation HIV integrase inhibitor, L-chicoric acid, is at least additive in combina tion with existing multi-drug regimens and suggest that HIV integrase will be an excellent target for combination therapy of HIV infection. (C) 1998 Elsevier Science B.V. All rights reserved.