Abstract
Raltegravir is the first publicly released HIV integrase inhibitor. In clinical trials, patients on a raltegravir-based highly active antiretroviral therapy (HAART) regimen were observed to have 70% less viraemia in the second-phase decay of viraemia than patients on an efavirenz-based HAART regimen. Because of this accelerated decay of viraemia, raltegravir has been speculated to have greater antiretroviral activity than efavirenz. Alternative explanations for this phenomenon are also possible. For example, the stage in the viral life cycle at which raltegravir acts might explain the distinct viral dynamics produced by this drug. In this report, we use a mathematical model of HIV viral dynamics to explore several hypotheses for why raltegravir causes different viral dynamics than efavirenz. Using the experimentally observed viral dynamics of raltegravir, we calculated constraints on the mechanisms possibly responsible for the unique viral dynamics produced by raltegravir. We predicted that the dominant mechanism for the 70% reduction in the second-phase viraemia is not antiviral efficacy but the stage of the HIV viral life cycle at which raltegravir acts. Furthermore, we found that the kinetic constraints placed on the identity of the virus-producing cells of the second phase were most consistent with monocytes/macrophages. Our model predictions have important implications for the motivation behind the use of raltegravir and our understanding of the virus-producing cells of the second-phase viraemia. Our results also highlight that the viral dynamics produced by different antiretroviral drugs should not be directly compared with each other.
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