Fosamprenavir: A review of its use in the management of antiretroviral therapy-naive patients with HIV infection

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 <400 copies/mL than those receiving a similar nelfinavir-based regimen. Results of the SOLO study showed similar reductions in viral load among patients who received once-daily ritonavir-boosted fosamprenavir and those treated with twice-daily nelfinavir, both in combination with twice-daily abacavir and lamivudine. In both trials, virological failure rates were at least twice as high with the nelfinavir-based regimen as they were with the fosamprenavir-based regimen. Fosamprenavir was generally well tolerated in clinical trials. The most common adverse events among patients treated with fosamprenavir, with or without ritonavir, plus abacavir and lamivudine were diarrhoea, nausea, vomiting, abdominal pain, drug hypersensitivity and skin rash. The incidence of diarrhoea was significantly lower with fosamprenavir-based therapy than with nelfinavir-based therapy in the NEAT and SOLO trials. The resistance profile of fosamprenavir is consistent with that of amprenavir. Amprenavir-resistant viral isolates from patients experiencing treatment failure with fosamprenavir-based therapy in the NEAT study showed little or no cross-resistance to several other PIs, and protease mutations commonly selected for by various other PIs were not observed. In the SOLO study, protease resistance mutations were not observed in viral isolates from patients experiencing treatment failure with ritonavir-boosted fosamprenavir-based therapy. In conclusion, fosamprenavir-based regimens have shown good antiviral efficacy and are generally well tolerated in antiretroviral therapy-naive patients with HIV infection. Available data on the resistance profile of the drug suggest that it may be used early in the course of therapy without compromising a range of future treatment options. The relatively low pill burden and lack of food restrictions with fosamprenavir may improve adherence to therapy. Further studies are needed to compare fosamprenavir with other PIs and to establish the long-term efficacy of fosamprenavir-based regimens. In conclusion, fosamprenavir appears to be a promising agent for the treatment of antiretroviral therapy-naive patients with HIV infection. Amprenavir prevents the formation of infectious HIV virions by inhibiting the viral protease. 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 incidence of abacavir resistance at week 48 (as determined by concomitant detection of reverse transcriptase mutation M184V and K65R or L74V) in the total population of abacavir-exposed patients from the NEAT and SOLO studies was less than 1%. Orally administered fosamprenavir is rapidly hydrolysed in the gut epithelium to amprenavir, the active moiety, and is not significantly absorbed itself. The mean area under the plasma amprenavir concentration-time curve to infinity (AUC∞) was 19.05 μg • h/mL and the mean maximum plasma amprenavir concentration (Cmax) of 4.26 μg/mL occurred 1.5 hours after oral administration of a single 1400mg dose of fosamprenavir (two 700mg tablets) to healthy, fasting volunteers. In single-dose studies, mean AUC∞ and C max of amprenavir (following a single dose of fosamprenavir 1400mg as tablets) were not affected by coadministration with a high-fat meal, and fosamprenavir may be taken with or without food. In antiretroviral therapy-naive patients with HIV infection, the pharmacokinetic profile of a single dose of fosamprenavir 1395mg was generally similar to that of fosamprenavir 1400mg in healthy volunteers, with a mean amprenavir AUC∞ of 22.8 μg • h/mL and Cmax of 4.64 μg/mL. Systemic exposure to amprenavir, in terms of AUC over the dosage interval (τ) at steady state, was similar after multiple oral administration of fosamprenavir 1395mg twice daily or amprenavir 1200mg twice daily to patients with HIV infection. At steady state, amprenavir Cmax was ≈30% lower with fosamprenavir than amprenavir, and trough amprenavir plasma concentrations (Cmin) were higher with fosamprenavir by a broadly similar margin. Fosamprenavir 1400mg twice daily achieves a mean steady-state amprenavir Cmin of 0.35 μg/mL (95% CI 0.27, 0.46) in patients with HIV infection, which exceeds the median in vitro 50% inhibitory concentration (IC50) previously determined from clinical HIV isolates. The volume of distribution of amprenavir is ≈430L in healthy volunteers, and plasma protein binding of amprenavir in vitro is ≈90%. Amprenavir is primarily metabolised by the cytochrome P450 (CYP) 3A4 pathway.