title: HIV reservoirs and immune surveillance evasion cause the failure of structured treatment interruptions: a computational study.
abstract: Continuous antiretroviral therapy is currently the most effective way to treat HIV infection. Unstructured interruptions are quite common due to side effects and toxicity, among others, and cannot be prevented. Several attempts to structure these interruptions failed due to an increased morbidity compared to continuous treatment. The cause of this failure is poorly understood and often attributed to drug resistance. Here we show that structured treatment interruptions would fail regardless of the emergence of drug resistance. Our computational model of the HIV infection dynamics in lymphoid tissue inside lymph nodes, demonstrates that HIV reservoirs and evasion from immune surveillance themselves are sufficient to cause the failure of structured interruptions. We validate our model with data from a clinical trial and show that it is possible to optimize the schedule of interruptions to perform as well as the continuous treatment in the absence of drug resistance. Our methodology enables studying the problem of treatment optimization without having impact on human beings. We anticipate that it is feasible to steer new clinical trials using computational models.
authors.affiliation: University of Amsterdam, Computational Science, Amsterdam, The Netherlands. E.Mancini@uva.nl
authors.forename: Emiliano
authors.initials: E
authors.lastname: Mancini
authors.forename: Filippo
authors.initials: F
authors.lastname: Castiglione
authors.forename: Massimo
authors.initials: M
authors.lastname: Bernaschi
authors.forename: Andrea
authors.initials: A
authors.lastname: de Luca
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Sloot
mesh_terms: D000465:Algorithms; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D004197:Disease Reservoirs / Q000821:virology*; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007157:Immunologic Surveillance; D018448:Models, Immunological; D015203:Reproducibility of Results; D016019:Survival Analysis; D017211:Treatment Failure