Modeling Pharmacodynamics on HIV Latent Infection: Choice of Drugs is Key to Successful Cure via Early Therapy

Source abstract

Highly active antiretroviral therapy has successfully controlled HIV replication in many patients. The treatment effectiveness may depend on the pharmacodynamics of antiretroviral drugs. In this paper, we integrate several drug-related parameters into an HIV infection model to investigate the effects of drug pharmacodynamics on the HIV latent reservoir and viral load dynamics. We showed that pharmacodynamic characteristics of drugs and the dosing schedule can significantly affect the outcome of either early or late treatment. Variations in each of the four studied parameters (the slope of the dose-response curve, the ratio of the maximum dosage to the 50% inhibitory concentration, the drug's half-life, and the dosing interval) can generate either an infection-free steady state or persistent infection when the other parameters remain unchanged. The global stability of the infection-free steady state and the viral persistence are shown to be governed by a viral invasion threshold that depends on the drug pharmacodynamics. Our results highlight that success of treatment, particularly pre-exposure prophylaxis or early treatment, may be determined by the choice of antiretroviral drugs in the treatment regimen; prophylaxis or very early treatment using drugs with a good pharmacodynamic profile has the potential to prevent or postpone the establishment of viral infection. In patients with established latent reservoir, late treatment can suppress the viral load to an undetectable level but cannot eradicate the virus. In this scenario, pharmacodynamic parameters and the dosing schedule can moderately change the viral load dynamics. However, the latent reservoir is hardly affected by them because it can be maintained by homeostasis of latently infected cells or other mechanisms rather than ongoing residual viral replication. These results support that drug pharmacodynamics need to be considered in studying HIV dynamics and in developing antiretroviral therapy against HIV infection.