Boosting immunity by antiviral drug therapy: A simple relationship among timing, efficacy, and success

Abstract

Drug therapies against persistent human infections such as hepatitis C virus, hepatitis B virus, and HIV fail to consistently eradicate the infection from the host. Hence, recent emphasis has shifted to the study of antiviral therapy aimed at boosting specific immune responses. It was argued that structured therapy interruptions were required to achieve this, because such regimes have shown promising results in early HIV infection. Using mathematical models, we show that, contrary to this notion, a single phase of drug therapy can result in the establishment of sustained immunity. We present a simple relationship between timing of therapy and efficacy of the drugs required for success. In the presence of strong viral suppression, we show that therapy should be stopped relatively early, and that a longer duration of treatment leads to failure. On the other hand, in the presence of weaker viral suppression, stopping treatment too early is detrimental, and therapy has to be continued beyond a time threshold. We discuss our modeling results primarily in the context of HCV therapy during chronic infection. Although the therapy regimes explored here also have implications for HIV, virus-mediated destruction of specific immune cells renders success unlikely during the chronic phase of the infection.

Underwhelming the Immune Response: Effect of Slow Virus Growth on CD8+-T-Lymphocyte Responses

“…Still, the present observations should help to draw more attention to this issue in future studies. This specific form of virus-host interaction may also be important during antiviral drug therapy, because long-lasting suppression of viral replication may lead to the loss of sufficiently stimulated cellular immune responses and, eventually, to treatment failure (26). Down-regulation of the virus growth kinetics (via a whole range of potential mechanisms), resulting in weaker CTL responses, might represent an effective strategy, in evolutionary terms, used by noncytopathic viruses to survive in immunocompetent hosts.…”

Tempo and mode of inhibitor–mutagen antiviral therapies: A multidisciplinary approach

“…Knowledge derived from in vitro studies of the response of pathogens to the action of one or a number of drugs might be combined with the information yielded by well-designed mathematical models involving the relevant mechanisms of action of and interaction among the drugs (9, 10), virus-host interactions (11), or role of the immune response (12). An important feature, rarely taken into account, is the intrinsic replicative ability of the pathogen.…”

Heterogeneity in chronic myeloid leukaemia dynamics during imatinib treatment: role of immune responses

“…It includes a population of cells that grow over time and that have the ability to impair immunity, as well as an immune response that reacts to this cell population and removes it. The mathematical model is part of a general class of models that share common properties (Komarova et al 2003). Results obtained from the model are therefore not dependent on the particular mathematical formulation used, but are robust.…”

“…As the number of cancer cells declines, withdrawal of antigenic stimulation causes a drop in immune responses. Such impairment dynamics have been explored extensively with mathematical models in the context of viral infections (Wodarz & Nowak 1999;Wodarz 2001;Komarova et al 2003), and more recently also in the context of CML (Kim et al 2008). The following will use a basic mathematical model that captures these assumptions.…”

“…A mathematical model is adapted that was previously published in the context of viral infections (Komarova et al 2003) and that captures the necessary assumptions. It includes a population of cells that grow over time and that have the ability to impair immunity, as well as an immune response that reacts to this cell population and removes it.…”