Bonhoeffer, Rembiszewski, Ortiz, Nixon, 2000

Model Status

This is the original unchecked version of the model imported from the previous CellML model repository, 24-Jan-2006.

Model Structure

Despite advances in the development of antiretroviral inhibitors, HIV treatment is still not 100 percent successful. Although combination therapy leads to a sustained reduction in virus load in many patients, complete removal of the virus is often prevented due to the latent nature of the virus. This latent period also means that patients have to remain on the powerful, expensive drugs for long, indefinite periods, which is expensive and associated with side effects and the evolution of drug resistant viruses. In view of these problems, new treatment strategies are needed. One such strategy is structured therapy interruption (STI), in which patients are put on and taken off therapy over a defined period of time (see the figure below). The theory behind this is to boost the patients' HIV-1-specific immune responses with autologous virus in a process similar to vaccination. The enhanced immunity may then help to clear the virus during treatment, or maintain a low level of the virus once therapy is finished.

Although STI has potential benefits, there are also associated risks such as evolved drug resistance. The authors of this current study, Bonhoeffer et al., believe that a mathematical framework could play a useful role in assessing the potential risks and benefits of STI. They develop three simple population dynamical models in order to assess the effect of structured therapy interruptions on:

The models have been described here in CellML (the raw CellML description of the Bonhoeffer et al. 2000 models can be downloaded in various formats as described in ).

The complete original paper reference is cited below:

Risks and benefits of structured antiretroviral drug therapy interruptions in HIV-1 infection, Sebastian Bonhoeffer, Michal Rembiszewski, Gabriel M. Ortiz, and Douglas F. Nixon, 2000, AIDS , 14, 2313-2322. (A full text (html) and PDF versions of the article are available to subscribers on the AIDS website.) PubMed ID: 11089619

The structured therapy interruption paradigm: if a patient's virus load declines much faster during highly active antiretroviral therapy than the decline in HIV-specific cytotoxic T lymphocyte (CTL) frequency, will there be a point at which the CTL outnumber the infected cells to an extent that the CTL can suppress the virus load when the therapy is stopped?

From model simulations the authors concluded that STI only leads to transient or sustained virus control if the immune effector cells increase during drug therapy. This increase must more than compensate for the increase in susceptible target cells induced during therapy. The risk of drug resistance evolving, or repopulating the pool of latent cells during drug free periods may be small if the virus population remains at levels below the baseline. However, if the virus load increases during the drug-free period to levels similar to or greater than the baseline before therapy, both these risks increase significantly.