title: HIV quasispecies dynamics during pro-active treatment switching: impact on multi-drug resistance and resistance archiving in latent reservoirs.
abstract: The human immunodeficiency virus (HIV) can be suppressed by highly active anti-retroviral therapy (HAART) in the majority of infected patients. Nevertheless, treatment interruptions inevitably result in viral rebounds from persistent, latently infected cells, necessitating lifelong treatment. Virological failure due to resistance development is a frequent event and the major threat to treatment success. Currently, it is recommended to change treatment after the confirmation of virological failure. However, at the moment virological failure is detected, drug resistant mutants already replicate in great numbers. They infect numerous cells, many of which will turn into latently infected cells. This pool of cells represents an archive of resistance, which has the potential of limiting future treatment options. The objective of this study was to design a treatment strategy for treatment-naive patients that decreases the likelihood of early treatment failure and preserves future treatment options. We propose to apply a single, pro-active treatment switch, following a period of treatment with an induction regimen. The main goal of the induction regimen is to decrease the abundance of randomly generated mutants that confer resistance to the maintenance regimen, thereby increasing subsequent treatment success. Treatment is switched before the overgrowth and archiving of mutant strains that carry resistance against the induction regimen and would limit its future re-use. In silico modelling shows that an optimal trade-off is achieved by switching treatment at days after the initiation of antiviral therapy. Evaluation of the proposed treatment strategy demonstrated significant improvements in terms of resistance archiving and virological response, as compared to conventional HAART. While continuous pro-active treatment alternation improved the clinical outcome in a randomized trial, our results indicate that a similar improvement might also be reached after a single pro-active treatment switch. The clinical validity of this finding, however, remains to be shown by a corresponding trial.
authors: Department of Mathematics and Computer Science, Freie Universität, Berlin, Germany. vkleist@zedat.fu-berlin.de
authors: Max
authors: M
authors: von Kleist
authors: Stephan
authors: S
authors: Menz
authors: Hartmut
authors: H
authors: Stocker
authors: Keikawus
authors: K
authors: Arasteh
authors: Christof
authors: C
authors: Schütte
authors: Wilhelm
authors: W
authors: Huisinga
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D018432:Drug Resistance, Multiple; D024882:Drug Resistance, Viral; D006678:HIV / Q000187:drug effects* / Q000472:pathogenicity*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008962:Models, Theoretical
chemical_list: D019380:Anti-HIV Agents