R E V I E W Enfuvirtide antiretroviral therapy in HIV-1 infection Christina MR Kitchen1 Miriam Nuño1 Scott G Kitchen2 Paul Krogstad3 1Department of Biostatistics, UCLA School of Public Health, Los Angeles, CA USA; 2Department of Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA USA; 3Departments of Pediatrics and Medical Molecular Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Correspondence: Christina MR Kitchen UCLA School of Public Health, 650 Charles E.Young Drive, Los Angeles, CA 90095-1772, USA Tel +1 310 825 7332 Fax +1 310 276 2113 Email cr@ucla.edu Abstract: It has been over 25 years since the ﬁrst diagnosis of what would be known as AIDS. Although great strides in anti-HIV therapeutics have been made, there is still a great need for antiretrovirals that are effective against drug-resistant HIV. Enfuvirtide (ENF) is the ﬁrst of a new class of fusion inhibitors to be approved by the US Food and Drug Administration for use in combination with other antiretroviral agents among HIV-1 infected patients with previous treatment experience. The inclusion of enfuvirtide in an optimized antiretroviral background regimen for the treatment of HIV-1 infected (treatment-experienced) patients followed the success of two critical clinical trials (TORO: T20 vs Optimized Regimen Only I and II). Even though injection-site reactions persisted in these trials, improved virological and immunological responses were observed among patients. Challenges associated with ENF treatment include the high cost of the drug, injection-site reactions, determining the optimal time to initiate treatment, and the potential for the selection of drug resistant mutants and viral evolution. ENF is a promising novel treatment for HIV infected individu- als whose choices for effective treatment are limited by previous treatment and resistance. Understanding the implications of viral ﬁtness and evolution in the presence of ENF treat- ment is crucial in determining effective and safe treatment regimens, particularly among treatment-experienced patients. Keywords: enfuvirtide, HIV, salvage therapy, drug resistance, gp41, evolution Introduction It has been over 25 years since what would be known as AIDS was ﬁrst recognized (Gottlieb et al 1981; Gottlieb 2006). Since then, antiretroviral therapy has greatly increased the lifespan of patients infected with HIV-1. However, drug resistance readily emerges during treatment, and new classes of drugs are needed to combat the virus. Enfuvirtide (also known as Fuzeon® or T-20; Roche) is the ﬁrst of a novel class of antiretrovirals called fusion inhibitors to receive approval for clinical use. Enfuvirtide (ENF) is a 36 amino-acid synthetic peptide that mimics the amino acids 127–162 present in heptad repeat-2 (HR-2) found in the HIV gp41 envelope glycoprotein subunit (Wild et al 1994; Chen et al 2002). ENF binds to residues in HR-1, blocking a conformational change in gp41 required for fusion of the lipid envelope of HIV with the cytoplasmic membrane of CD4 T cells, thus preventing viral entry (Chen et al 1995; Moore and Doms 2003). ENF was approved in 2003 for use in patients who are treatment-experienced and have advanced HIV-1 infec- tion (Fletcher 2003; Matthews et al 2004) adding a much-needed fourth class of drugs to treat HIV infection. In the current review we will detail the results from ENF clinical trials. We will then review the clinical management of ENF based regimens including dosing, clinical usage, resistance and cross-resistance and usage pertaining to non-clade B infections. We will then discuss the evolutionary consequences of ENF treatment and we will ﬁnish with a summation of these subjects. Therapeutics and Clinical Risk Management 2008:4(2) 433–439 © 2008 Dove Medical Press Limited. All rights reserved 433