Fosamprenavir

Abstract

Fosamprenavir (GW433908, Lexiva™, Telzir®) is an oral prodrug of the protease inhibitor (PI) amprenavir, with a reduced daily pill burden. Fosamprenavir, in combination with other antiretroviral agents, is indicated for the treatment of patients with HIV infection, particularly those who have not previously received antiretroviral therapy. Viral load reductions were at least as great with fosamprenavir-based regimens as those achieved with nelfinavir-based regimens in two large, 48-week, randomised, multicentre trials in antiretroviral therapy-naive patients with HIV infection. In the NEAT study, more patients receiving twice-daily fosamprenavir in combination with abacavir and lamivudine achieved HIV RNA levels In vitro, amprenavir produced 50% inhibition of HIV replication at concentrations of 0.012-0.08 μmol/L in acutely infected cell lines. Amprenavir has synergistic activity against HIV in combination with a number of nucleoside reverse transcriptase inhibitors (NRTIs) and has additive effects with some protease inhibitors (PIs). Amprenavir has also shown no significant cytotoxicity against human T- or B-cell lines or bone marrow progenitor cells in vitro. Limited preclinical data have suggested that amprenavir has little or no effect on lipid metabolism in vitro, in murine models or in healthy volunteers, although lipodystrophy has been observed in patients receiving fosamprenavir in clinical trials. Protease resistance mutations selected during therapy with unboosted fosamprenavir in the NEAT study (I54L/M, V32I + I47V, and M46I) were generally consistent with those selected by amprenavir in another trial (I50V, I54L/M, V32I + I47V or I84V, each usually accompanied by accessory mutations such as M46I/L). The I50V mutation (which also contributes to lopinavir resistance) was not selected by fosamprenavir treatment during the NEAT trial, and continuation of treatment with fosamprenavir despite ongoing viral replication resulted in a single case of I50V emergence. Mutations selected for by unboosted fosamprenavir conferred little or no cross-resistance to several other PIs (indinavir, lopinavir, nelfinavir, ritonavir or saquinavir), and mutations characteristic of various other PIs (D30N, I54V, V82A/T/S and L90M) were not detected in viral isolates from patients treated with fosamprenavir. At the time of data assessment, 60 of the 112 patients who successfully completed the NEAT study and remained on fosamprenavir-based therapy as part of a follow-up study have been assessed at week 96. Mutations associated with fosamprenavir resistance were detected in only three plasma samples (I54L, V32I + I47V and I50V) and minimal cross-resistance to other protease inhibitors was observed. In the SOLO trial, fosamprenavir boosted with low-dose ritonavir (fosamprenavir/ritonavir) did not select any protease resistance mutations, whereas 50% of patients with virological failure while receiving nelfinavir-based therapy had viral isolates with protease resistance mutations (p < 0.001). There was also a significant difference favouring fosamprenavir/ritonavir-over nelfinavir-based therapy for the incidence of mutations selected for by lamivudine (p < 0.001). At the time of data assessment, 115 of the 210 patients who completed the SOLO study and remained on fosamprenavir/ritonavir-based therapy as part of a follow-up study have reached the week 96 assessment, and resistance analysis showed no evidence for the emergence of protease resistance-associated mutations. The cumulative...