The impact of resistance on viral fitness and its clinical implications

Excerpt

The primary goal of antiretroviral treatment is to durably suppress viral replication in order to promote immune reconstitution and reduce AIDS-related morbidity and mortality. In HIV-1-infected patients with a history of treatment failure, the selection of drug-resistant and multidrug-resistant virus may not allow complete suppression of viral replication. In these patients, immunological stability is often observed despite ongoing viral replication, when drug-resistant virus with lower fitness is selected by antiretroviral drug pressure [1]. In fact, when HIV-1 develops resistance to antiretroviral drugs through the acquisition of mutations in the pol gene, it often pays a price in terms of reduced replication capacity and reduced pathogenicity [2,3]. The deleterious effects on viral fitness associated with the acquisition of drug resistance presumably result from mutation-induced structural changes in the binding of the natural substrate and in the catalytic activity of the reverse transcriptase (RT) and protease [4,5]. However, the degree of impairment of viral replication appears to vary widely among viral strains that are resistant to antiretroviral agents (see Figure 1) [6,7]. Additional data suggest also that viral fitness varies among clinical isolates from drug-naive individuals, reflecting natural genetic polymorphisms present in each viral strain [8].

Evidence to date clearly indicates that several drug-resistance mutations are associated with reduced ability of HIV-1 to replicate. More recent data also suggest that, whereas drug susceptibility remains the most important determinant of treatment response, reduced viral fitness can be exploited to derive a clinical benefit, especially in settings in which patients have limited therapeutic alternatives.