video: Model simulation (100 days) of an extremely low dose of pritelivir (5 mg daily), which exerts almost no effect on viral growth. The bottom left panel is a map of the human genital tract divided into 200 regions, showing the density of protective T cells within each region. The bottom right panel is the effective reproductive number within each model region: areas where the virus is rapidly eliminated are grey or black, while areas where the virus is growing are green. As the simulation progresses, large episodes eventually occur (at day 118 and 348) because large portions of the genital tract are left unprotected These episodes are represented with the red line in the upper left panel showing viral level, and regions of the map in the upper right panel with viral load. This material relates to a paper that appeared in the 3 February 2016, issue of Science Translational Medicine, published by AAAS. The paper, by J.T. Schiffer at University of Washington in Seattle, WA, and colleagues was titled, "Mathematical modeling of herpes simplex virus-2 suppression with pritelivir predicts trial outcomes." view more
Credit: J.T. Schiffer et al., <i>Science Translational Medicine</i> (2016)
A mathematical model may offer a valuable tool for selecting the proper dose of antiviral drugs for further testing in clinical trials. Researchers showed that the model can accurately predict the results of a clinical study of a herpes drug and pinpoint the most effective dose for treatment. Such a tool could help improve patient outcome and reduce the high costs, time, and failure rate associated with drug development, the researchers say. Therapies often fail to move beyond late-stage clinical testing, in part because choosing the proper dose needed for a drug to be effective is often an imprecise science. Current methods for estimating antiviral drug dosing test the drug's potency against a virus in a plate of cells. However, in vitro or cell experiments neglect the complex immune response against the virus that occurs during human infection. In search of a better approach, Joshua Schiffer and colleagues designed a mathematical model that captures the interplay between the virus, the immune response, and drug. They used their model to determine the optimal dose for pritelivir, an experimental drug that targets herpes simplex virus-2 (HSV-2), the leading cause of genital herpes. Currently, herpes drugs like pritelivir only partially suppress the release of the virus in the genital tract. The model the researchers developed accurately reproduced results from a phase 2 clinical trial of 150 patients treated with pritelivir at four different doses. Suppressing viral shedding by 50% required a greater drug concentration, the researchers found, than published in vitro studies on pritelivir dose selection would suggest. Model simulations revealed that at increasing doses, the drug not only blocks viral replication, but also indirectly curbs the spread of HSV-2 within genital ulcers and from ulcers to new infection sites. The model also predicted outcomes of a separate trial of pritelivir, validating the model's approach. The researchers say that by harnessing data from phase 2 clinical studies of antiviral drugs, their model could help optimize dose selection for late-stage trials.
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Journal
Science Translational Medicine