Amprenavir is an HIV-1 protease inhibitor, the first in vitro activity studies of which were published in 1995. During in vivo development, it became clear that the pharmacokinetics of the drug would result in patients taking a large number of pills daily. The first comparative studies of amprenavir versus other protease inhibitors showed it had comparatively weak activity. Thus, studies using low doses of ritonavir to enhance the pharmacokinetic profile of amprenavir were first communicated in 2000. Only a small number of clinical trials in HIV-1-infected patients have been published. The pharmacokinetics of amprenavir have been documented in both healthy individuals and in HIV-1-infected patients. Amprenavir trough plasma concentrations increase 3- to 10-fold and the area under the concentration-time curve (AUC) increases 2- to 3-fold when using amprenavir 450 or 600 mg combined with ritonavir 100mg twice daily. Peak concentrations of amprenavir are less influenced by ritonavir coadministration, with a 1- to 2-fold increase. As there is no pharmacokinetic advantage to increasing ritonavir doses, the combination has only been used with low doses of ritonavir (100mg twice daily or 200 mg once or twice daily). Concomitant use of currently available non-nucleoside reverse transcriptase inhibitors (NNRTIs)--efavirenz or nevirapine--is possible when amprenavir is coadministered with ritonavir, despite the pharmacokinetic interactions described when they are used with amprenavir alone. Fosamprenavir (GW 433908) is a prodrug of amprenavir primarily metabolised to amprenavir in the epithelial cells of the intestine. At steady state, plasma trough concentrations and AUC are slightly greater with fosamprenavir (two pills of 700 mg twice daily) than amprenavir (eight soft gel capsules of 150 mg twice daily). The clinical adverse effects of amprenavir are similar whether administered unboosted or in combination with ritonavir. Skin rashes do not appear to be more frequent. With regard to lipid profiles, the addition of ritonavir to amprenavir induces an increase in cholesterol and triglyceride levels; however, prospective comparative studies are lacking. In short-term prospective trials in antiretroviral-naive individuals, virological suppression with highly active antiretroviral therapy containing amprenavir plus ritonavir is similar to or higher than with unboosted amprenavir, with a smaller pill intake. Few comparative data are available in treatment-experienced patients. In several small studies, different salvage regimens which included amprenavir plus ritonavir achieved undetectable viral levels in half of the patients. Although the I50V amino acid substitution is the key mutation conferring resistance to amprenavir, the accumulation of several mutations is needed to increase the IC50 (concentration that produces 50% inhibition) of amprenavir. When used with ritonavir, the accumulation of six or more mutations among L10F/I/V, K20M/R, E35D, R41K, I54V, L63P, V82A/F/T/S and I84V leads to clear decrease in viral response to treatment. In salvage regimens, coadministration of amprenavir with lopinavir/ritonavir induces variations in lopinavir and amprenavir concentrations (decrease or increase in both drug concentrations) compared with the combination with ritonavir alone. Currently, close pharmacokinetic follow-up is mandatory when such combinations are used. There are sufficient data available today to support coadministration of reduced doses of amprenavir with low doses of ritonavir. Compared with amprenavir alone, this results in the administration of fewer pills with equivalent or higher efficacy, but without new clinical adverse effects. The concentrations of amprenavir achieved are high enough for use in treatment-experienced patients who have an accumulation of amino acid substitutions in the HIV-1 protease gene. It also allows combinations with NNRTIs. The pharmacokinetic properties of fosamprenavir and the first clinical trials in treatment-naive and treatment-experienced patients should allow it to be considered as a better alternative to amprenavir in countries where fosamprenavir is already available.