Impact of non-adherence to antiretroviral therapy in HIV-infected children
C. Piana (1), M. Danhof (1), O.E. Della Pasqua (1,2)
(1) Division of Pharmacology, Leiden/Amsterdam Centre for Drug Research, The Netherlands; (2) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, UK
Objectives: Data exist showing failure of treatment with antiretrovirals due to inadequate adherence to the prescribed dosing regimen. Several studies have been performed to assess whether high rates of adherence are necessary to achieve and maintain viral suppression during the course of therapy [1, 2, 3]. However, none of these studies have explored compliance in a systematic manner, identifying which drugs are more likely to be affected by poor adherence. The aim of this investigation was therefore to evaluate the forgiveness of antiretroviral therapy to variable compliance, taking into account the differences in pharmacokinetics and pharmacodynamic properties of currently used drugs.
Methods: Simulation scenarios were evaluated using a hypothetical population of HIV-infected children (n=100) aged between three months and eleven years. Published pharmacokinetic and pharmacodynamic models were integrated with an established model for viral replication to predict treatment outcome based on different degrees of adherence to therapy for each class of drugs used in first-line therapy (non-nucleoside reverse transcriptase inhibitors and nucleoside reverse transcriptase inhibitors). The measures of interest were viral load and CD4 cell count.Text regarding objectives.Text regarding methods.
Results: Preliminary results suggest that efavirenz, a non-nucleoside reverse transcriptase inhibitor with long half-life and high potency, allows for variable quality of compliance, such as delays in drug administration, whilst it is more susceptible to interruption of therapy for long periods (2-3 weeks).
Conclusions: Despite its relevance in therapeutics, the implications of poor compliance and most importantly the degree of forgiveness of antiretrovirals has not been assessed in a quantitative manner. Our results show that simulations can be applied as a tool to explore non-adherence to treatment. The use of this model-based approach provides a framework for the optimisation of the dosing regimens for antiretroviral drugs, unravelling the set of pharmacokinetic and pharmacodynamic properties that are required for forgiveness.
References:
[1] Bangsberg D, Moss A, Deeks S. Paradoxes of adherence and drug resistance to HIV antiretroviral therapy. Journal of Antimicrobial Chemotherapy (2004) 53, 696-699
[2] Shuter J. Forgiveness of non-adherence to HIV-1 antiretroviral therapy. Journal of Antimicrobial Chemotherapy (2008) 61,769-773
[3] Vrijens B, Goetghebeur E, de Klerk E, Rode R, Mayer S, Urquhart J. Modelling the association between adherence and viral load in HIV-infected patients. Stat Med. (2005) 24,2719-31
