ANTI-HIV ACTIVITY OF ADEFOVIR (PMEA) AND PMPA IN COMBINATION WITH ANTIRETROVIRAL COMPOUNDS - IN-VITRO ANALYSES

Adefovir (PMEA, 9-(2-phosphonomethoxyethyl)adenine), an acyclic nucleo side phosphonate analogue is active against retroviruses, hepadnaviru ses and herpesviruses. Adefovir dipivoxil, an orally bioavailable prod rug of adefovir is currently in phase III clinical trials for the trea tment of HIV and phase II clinical trials for the treatment of HBV inf ections. PMPA (9-(2-phosphonomethoxypropyl)adenine) is a related acycl ic nucleoside phosphonate analogue that has demonstrated potent anti-S IV activity in rhesus macaques and recently has shown marked anti-HIV activity in a phase I clinical study. Since the standard of care for A IDS patients has become combination therapy, the effects of other anti retroviral compounds (d4T, ddC, AZT, ddI, 3TC, nelfinavir, ritonavir, indinavir, and saquinavir) on the anti-HIV activity of adefovir and PM PA were investigated in vitro. Adefovir and PMPA both demonstrated' st rong synergistic anti-HIV activity in combination with AZT. Adefovir d emonstrated minor to moderate synergistic inhibition of HIV replicatio n in combination with PMPA, d4T, ddC, nelfinavir, ritonavir, and saqui navir. PMPA demonstrated minor synergistic inhibition of HIV replicati on in combination with ddI and nelfinavir (and adefovir). All other co mbinations showed additive inhibition of HIV replication in vitro. Imp ortantly, no antagonistic interactions were measured for any of the ad efovir or PMPA combinations. (C) 1997 Elsevier Science B.V.