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HIV prevention trial design in an era of effective pre-exposure prophylaxis

Cutrell, A; Donnell, D; Dunn, DT; Glidden, DV; Grobler, A; Hanscom, B; Stancil, BS; ... Cuffe, RL; + view all (2017) HIV prevention trial design in an era of effective pre-exposure prophylaxis. HIV Clinical Trials 10.1080/15284336.2017.1379676. (In press). Green open access

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Abstract

Pre-exposure prophylaxis (PrEP) has demonstrated remarkable effectiveness protecting at-risk individuals from HIV-1 infection. Despite this record of effectiveness, concerns persist about the diminished protective effect observed in women compared with men and the influence of adherence and risk behaviors on effectiveness in targeted subpopulations. Furthermore, the high prophylactic efficacy of the first PrEP agent, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), presents challenges for demonstrating the efficacy of new candidates. Trials of new agents would typically require use of non-inferiority (NI) designs in which acceptable efficacy for an experimental agent is determined using pre-defined margins based on the efficacy of the proven active comparator (i.e. TDF/FTC) in placebo-controlled trials. Setting NI margins is a critical step in designing registrational studies. Under- or over-estimation of the margin can call into question the utility of the study in the registration package. The dependence on previous placebo-controlled trials introduces the same issues as external/historical controls. These issues will need to be addressed using trial design features such as re-estimated NI margins, enrichment strategies, run-in periods, crossover between study arms, and adaptive re-estimation of sample sizes. These measures and other innovations can help to ensure that new PrEP agents are made available to the public using stringent standards of evidence.

Type: Article
Title: HIV prevention trial design in an era of effective pre-exposure prophylaxis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1080/15284336.2017.1379676
Publisher version: http://doi.org/10.1080/15284336.2017.1379676
Language: English
Additional information: Copyright © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-ncnd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
Keywords: HIV-1, PrEP, TDF/FTC, non-inferiority trials, pre-exposure prophylaxis, tenofovir disoproxil fumarate/emtricitabine, trial design
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/10033898
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