Enfuvirtide Antiviral Activity despite Rebound Viremia and Resistance Mutations: Fitness Tampering or a Case of Persistent Braking on Entering?

Abstract

Combination antiretroviral therapy has revolutionized the care of HIV1-infected individuals, producing profound improvements in morbidity and mortality. Therapy does not, however, cure HIV infection, and the goal of combination therapy remains the suppression of HIV-1I replication below the limit of detection. Despite a growing array of antiretroviral therapy options, virologic suppression is difficult for many patients to achieve, and treatment of drug-resistant virus is a critical challenge confronting HIV therapeutics. Resistance emerges as a result of both virologic and clinical factors. HIV-1 replication is rapid and error prone, yielding a large, genetically diverse virus population. As a consequence, many single amino-acid changes conferring drug resistance may preexist as low frequency polymorphisms before the initiation of antiviral therapy [1, 2]. Individuals who received their diagnosis of HIV infection before the widespread use of combination antiretroviral regimens often received serial therapy with 1 or 2 agents, resulting in the accumulation of additional drugresistance mutations to each new approved agent. Poor adherence to therapy has been associated with higher rates of virologic failure and the emergence of drug resistance, and sequential regimens for drug-resistant virus fail in patients [36] more often than initial regimens in drug-naive individuals [7-9]. Current therapeutic regimens to treat highly drug-resistant HIV-1 remain inadequate. The recommendation that regimens to treat drug-resistant HIV1 should include at least 2 new drugs to which patients have not been exposed [10] is often impossible to fulfill if patients have extensive prior therapy experience. Recently, several studies have suggested the presence of residual virologic activity for some antivirals even in the presence of mutations [11-14]. In this issue of the Journal of Infectious Diseases, Deeks et al. [15] report the presence of virologic benefit of enfuvirtide (T-20) in the presence of rebound viremia and enfuvirtide resistance mutations. Enfuvirtide is the first of a new class of