title: Assessing the impact of adherence to anti-retroviral therapy on treatment failure and resistance evolution in HIV.
abstract: The adherence of patients to therapy is a crucial factor for successful HIV anti-retroviral therapy. Imperfect adherence may lead to treatment failure, which can cause the emergence of resistance within viral populations. We have developed a stochastic model that incorporates compartments of latently infected cells and virus genotypes with different susceptibilities to three simultaneously used drugs. With this model, we study the impact of several key parameters on the probability of treatment failure, i.e. insufficient viral suppression, and the emergence of resistance. Specifically, we consider the impact of drug dosage, drug half-lives, fitness costs for resistance, different basic reproductive numbers of the virus and the influence of pre-existing mutations under various levels of adherence. Furthermore, we also investigate the influence of different temporal distributions of non-adherent days (drug holidays) during a treatment. Factors that promote resistance evolution include a high reproductive number, extended drug holidays and poor adherence. Pre-existing mutations only have a substantial effect if they confer resistance against more than one drug. Overall, our study highlights the importance of the interactions between imperfect adherence, pharmacodynamics, pharmacokinetics and latently infected cells for our understanding of drug resistance and therapy failure in HIV anti-retroviral therapy.
authors.affiliation: Institute of Integrative Biology, ETH Zurich, 8092 Zurich, Switzerland. dominique.cadosch@env.ethz.ch
authors.forename: Dominique
authors.initials: D
authors.lastname: Cadosch
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bonhoeffer
authors.forename: Roger
authors.initials: R
authors.lastname: Kouyos
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D024921:Drug Resistance, Multiple, Viral / Q000187:drug effects / Q000235:genetics; D019143:Evolution, Molecular; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055118:Medication Adherence; D008954:Models, Biological; D009154:Mutation; D017211:Treatment Failure