Constraints on the dominant mechanism for HIV viral dynamics in patients on raltegravir.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Sedaghat
Ahmad R
AR
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sedaghat@jhmi.edu
Siliciano
Robert F
RF
Wilke
Claus O
CO
D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D006678:HIV / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000821:virology*; D019428:HIV Integrase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008954:Models, Biological; D011760:Pyrrolidinones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000068898:Raltegravir Potassium; D014766:Viremia / Q000188:drug therapy / Q000209:etiology; D016662:Virus Integration / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium