BACKGROUND Drug resistance continues to be a major challenge in the treatment of HIV-1 infection. Virtually all currently available antiretroviral medications inhibit the viral reverse transcriptase or protease. Enfuvirtide is the first fusion inhibitor approved by the US Food and Drug Administration for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients. OBJECTIVE This paper describes the pharmacologic properties and clinical usefulness of enfuvirtide. METHODS Relevant information was identified through searches of MEDLINE (1990 to October 2003), International Pharmaceutical Abstracts (1970 to October 2003), and meeting abstracts of major HIV/AIDS conferences (1996-2003) using the search terms enfuvirtide, pentafuside, T-20, DP-178, and fusion inhibitor. RESULTS In vitro, enfuvirtide exhibits activity against HIV-1 isolates that are resistant to all other classes of anti-retroviral medications. Enfuvirtide blocks the entry of HIV-1 into host cells by interfering with virus-cell fusion, making it unique among licensed antiretroviral medications. In human adults, enfuvirtide has a volume of distribution of 5.48 L, is highly bound to plasma protein (92%), has a plasma elimination half-life of 3.8 hours, and is catabolized by peptidases and proteinases in various tissues. Dose adjustment does not appear necessary on the basis of age, race, or body weight, but may be warranted in women weighing <50 kg. A literature review did not identify any data on the disposition of enfuvirtide in patients with hepatic or renal insufficiency. Clinical trials suggest that enfuvirtide reduces plasma HIV-1 RNA levels in highly treatment-experienced patients taking an optimized antiretroviral regimen. Pivotal trials indicated a mean change in HIV-1 RNA of -1.48 log(10) copies/mL in the enfuvirtide arm at week 48, compared with -0.63 log(10) copy/mL in the control arm ( P<0.001 ). The mean absolute increase on CD4 cell count was 46 cells/mm(3) (91 cells/mm(3)) in the enfuvirtide arm vs 45 cells/mm(3) in the control arm; P<0.001 ). The most commonly reported (>15 cases per 100 patient-years of exposure) adverse events (AEs) in clinical trials included injection-site reactions, diarrhea, nausea, fatigue, insomnia, peripheral neuropathy, headache, vomiting, and fever. The most commonly reported (> or =2%) laboratory abnormalities (grade III or IV) were eosinophilia, anemia, and increases in amylase, lipase, triglycerides, creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase. In clinical trials, serious AEs leading to study discontinuation occurred in 12.9% ( 114/885 ) of patients in the enfuvirtide arm, compared with 10.7% ( 12/112 ) in the control arm ( P = NS ). The recommended dosage of enfuvirtide is 90 mg SC BID in adults and 2 mg/kg SC BID in children. Efficacy studies in children are ongoing. CONCLUSIONS Although additional studies are needed, enfuvirtide appears to be a promising agent, in combination with other antiretroviral agents, for the treatment of HIV infection in treatment-experienced patients.