Schomaker, Michael;
Denti, Paolo;
Bienczak, Andrzej;
Burger, David;
Diaz, Ivan;
Gibb, Diana;
Walker, Ann;
(2024)
Determining Targets for Antiretroviral Drug Concentrations: a Causal Framework Illustrated with Pediatric Efavirenz Data from the CHAPAS-3 Trial.
Pharmacoepidemiology and Drug Safety
, 33
(12)
, Article e70051. 10.1002/pds.70051.
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Abstract
Background Determining a therapeutic window for maintaining antiretroviral drug concentrations within an appropriate range is required for identifying effective dosing regimens. The limits of this window are typically calculated using predictive models. We propose that target concentrations should instead be calculated based on counterfactual probabilities of relevant outcomes and describe a counterfactual framework for this. Methods The proposed framework is applied in an analysis including longitudinal observational data from 125 HIV-positive children treated with efavirenz-based regimens within the CHAPAS-3 trial, which enrolled children < 13 years in Zambia/Uganda. A directed acyclic graph was developed to visualize the mechanisms affecting antiretroviral concentrations. Causal concentration-response curves, adjusted for measured time-varying confounding of weight and adherence, are calculated using g-computation. Results The estimated curves show that higher concentrations during follow-up, 12/24 h after dose, lead to lower probabilities of viral failure (> 100 c/mL) at 96 weeks of follow-up. Estimated counterfactual failure probabilities under the current target range of 1–4 mg/L range from 24% to about 2%. The curves are almost identical for slow, intermediate and extensive metabolizers and show that a mid-dose concentration level of ≥ 3.5 mg/L would be required to achieve a failure probability of < 5%. Conclusions Our analyses demonstrate that a causal approach may lead to different minimum concentration limits than analyses that are based on purely predictive models. Moreover, the approach highlights that indirect causes of failure, such as patients' metabolizing status, may predict patients' failure risk, but do not alter the threshold at which antiviral activity of efavirenz is severely reduced.
| Type: | Article |
|---|---|
| Title: | Determining Targets for Antiretroviral Drug Concentrations: a Causal Framework Illustrated with Pediatric Efavirenz Data from the CHAPAS-3 Trial |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/pds.70051 |
| Publisher version: | https://doi.org/10.1002/pds.70051 |
| Language: | English |
| Additional information: | © 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | antiretroviral therapy; causal inference; continuous interventions; pediatrics; target concentrations. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10198701 |
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