Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes

Key Points The elucidation of the HIV life cycle from the mid-1980s onwards revealed targets for therapeutic intervention, ultimately leading to the development of several classes of antiretroviral drugs (ARVs), which are now usually combined in specific multidrug regimens. However, such therapy eventually fails in the vast majority of patients and is typically associated with the emergence of drug resistance. Agents that target different steps in the HIV life cycle could address this problem. HIV-mediated fusion of the virus to the target host cell is a multi-step process involving a series of conformational changes in the envelope glycoproteins of HIV, gp120 and gp41. Enfuvirtide, a 36-amino-acid peptide derived from gp41, was found to have antiviral properties. It was subsequently shown that enfuvirtide binds to a region of gp41 and disrupts the conformational changes associated with virus–host-cell fusion, thereby blocking virus entry and inhibiting viral replication. The major unmet need is for antiretroviral drugs with activity against HIV strains resistant to existing ARV drugs. The clinical development programme for enfuvirtide thus focused on patients that had been exposed to and/or had documented resistance to each of the three existing classes of ARVs. In the two pivotal Phase III trials, enfuvirtide plus an individually optimized background regimen (consisting of 3–5 ARVs) demonstrated superior virological and immunological activity to an individually optimized background regimen alone after 24 weeks. Accelerated approval was granted to enfuvirtide in the United States and Europe on the basis of these results. Data collected after 48 weeks from the Phase III trials confirmed the durability of enfuvirtide added to an optimized background regimen. Highly active antiretroviral therapy (HAART) based on combinations of drugs that target key enzymes in the life-cycle of human immunodeficiency virus (HIV) has considerably reduced morbidity and mortality from HIV infection since its introduction in the mid-1990s. However, the growing problem of the emergence of HIV strains that are resistant not only to individual drugs, but to whole drug classes, means that agents with new mechanisms of action are needed. Here, we describe the discovery and development of enfuvirtide (Fuzeon), the first drug to inhibit the entry of HIV-1 into host cells.