Resistance to Enfuvirtide and Other HIV Entry Inhibitors

At the turn of the twenty-fi rst century, only three classes of antiretrovirals were available for the treatment of HIV: nucleoside reverse transcriptase inhibitors (nRTIs), nonnucleoside RTIs, and protease inhibitors (PIs). Although combinations of these agents often provided potent suppression of HIV-1 RNA, and had dramatically improved clinical outcomes for many patients (1), the limitations of highly active antiretroviral therapy based on the available compounds had becoming increasingly apparent and problematic. Those limitations included adverse effects associated with treatment (2, 3), signifi cant drug-drug interactions (4), and the selection of drug-resistant viruses with extensive intraclass cross-resistance (5). Consequently, there was a clear need for new classes of antiretroviral agents with both improved safety and tolerability profi les, and which act on alternative targets and thereby circumvent the problems associated with intraclass cross-resistance. The fi rst such drug to be introduced in the new millennium was the HIV-1 fusion inhibitor enfuvirtide (formerly known as T-20), which became available in 2003. Enfuvirtide, when used in combination with previously available antiretrovirals, provided signifi cant virological and immunological benefi ts to patients with few remaining treatment options (6, 7). As of early 2007, the entry inhibitors maraviroc and vicriviroc, which target CCR5 binding, were under review for regulatory approval or were in late-stage clinical trials (8-10). Although not discussed in this chapter, compounds targeting the viral integrase had also shown promising results in Phase 2 clinical studies and were in the late stages of clinical development (11).