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: Suboptimal adherence to antiretroviral therapy is the most common cause of viral resistance. Despite the magnitude of this problem, precise measures of forgiveness to non-adherence for antiretroviral combination treatments are still lacking. Furthermore, a distinction between the impact of different patterns of non-adherence, such as treatment interruptions or delays in dose intake, has never been performed in a systematic manner. The aim of this analysis is to assess the impact of different patterns of non-adherence on treatment outcome for the antiretroviral combinations currently used as first-line therapy in HIV-infected children.
Methods: Simulation scenarios were evaluated using a hypothetical population of HIV-infected children (n=100) 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 and different patterns of non-adherence to therapy. A logistic regression was used to incorporate the relation between sub-therapeutic drug levels and the probability of developing resistance. The duration of the hypothetical trial was 24 weeks. Viral load at the end of the trial was considered as primary endpoint.
Results: Preliminary results suggest that non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens (efavirenz-lamivudine-abacavir) are susceptible to repeated treatment interruptions of one or two weeks, while allow for delays in drug intake up to 6 hours.
Conclusions: Despite its relevance in therapeutics, the degree of forgiveness of antiretroviral combinations has not been assessed in a quantitative manner. Our results show that simulations can be applied as a tool to explore the impact of different patterns of non-adherence to combination treatment. The use of a model-based approach provides a framework to optimise dosing regimens in paediatric patients and to guide regimen choice taking into account different patterns of adherence.
References:
[1] Bangsberg D. Preventing HIV antiretroviral resistance through 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
Reference: PAGE 21 () Abstr 2524 [www.page-meeting.org/?abstract=2524]
Poster: Paediatrics