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The introduction of enfuvirtide (FUZEON) represents an important advance in the treatment of therapy-experienced patients with HIV-1 infection. However, parenteral self-administration, and the advanced disease and antiretroviral experience of patients currently most needing enfuvirtide introduce unique usage considerations.Enfuvirtide has been shown to provide clinically relevant improvements in CD4 cell counts and reductions in HIV viraemia across all subgroups of treatment-experienced patients studied, including those taking few or no other active drugs. However, optimal outcome results from initiation when the CD4 cell count is above 100 × 106 cells/l and viraemia below 1 × 105 copies/ml, as part of a newly constructed third or fourth antiretroviral regimen in combination with one or two other antiretrovirals to which the virus remains sensitive. Resistance testing should be used where available to guide background drug selection.Where insufficient options for an effective background exist, enfuvirtide should still be considered and treatment undertaken with the aim of achieving an immunological or clinical response, despite the unlikelihood of a sustained virological outcome. Similarly, where there is no viable alternative treatment, enfuvirtide should be continued following virological failure wherever ongoing immunological or clinical benefit is discerned.Injection site reactions (ISRs) are common on enfuvirtide and will affect almost all patients. ISRs are manageable and seldom activity- or treatment-limiting. Bacterial pneumonia and systemic hypersensitivity reactions have also been reported uncommonly.A structured series of patient visits with a healthcare professional provides an atmosphere of ongoing training and support that may prevent ‘injection fatigue', maintain adherence and minimise the incidence of ISRs. An initial investment in establishing such procedures can be expected to yield significant returns in patient confidence and benefit on enfuvirtide.