When more is less.

Abstract

Landmark studies on the dynamics of HIV-1 infection, conducted nearly a decade ago, provided the theoretical framework on which the modern approach to combination antiretroviral therapy is based [1]. It is now accepted dogma that the high turnover rate of the virus, coupled with a high mutation rate—a consequence of the low fidelity of reverse transcriptase—leads to the accumulation of mutations in the viral quasispecies over time. According to this model, individual drug-resistance mutations are represented many times in the quasispecies; doublemutants are less common, and specific triple mutants are relatively rare [2]. Antiretroviral regimens consisting of several drugs with nonoverlapping resistance patterns erect a genetic barrier to resistance, because multiple mutations—which are unlikely to be preexisting in any single viral genome—are needed to reduce activity of the regimen. Because the level of plasma HIV-1 RNA at steady state is a function of the replication rate and because the replication rate is a determinant of the mutation rate, it is reasonable to assume that patients with high plasma HIV-1 RNA levels are more likely to harbor preexisting drug-resistant variants than are patients with lower virus loads. Likewise, patients with advanced HIV-1 disease may be at greater risk for the development of drug-resistant virus. In such patients, the genetic barrier of triple combination therapy might not suffice to prevent emergence of resistance and ensure durable suppression of virus replication. Indeed, for certain 3-drug combination regimens, high virus load and low CD4 cell count are associated with a greater risk of treatment failure [3].