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      Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy

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          Abstract

          The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug–polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.

          Abstract

          Poor adherence to daily antiretrovirals can significantly affect treatment efficacy, but oral long-acting antiretrovirals are currently lacking. Here, the authors develop a once-weekly oral dosage form for anti-HIV drugs, assess its pharmacokinetics in pigs, and model its impact on viral resistance and disease epidemics.

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          Non-adherence to highly active antiretroviral therapy predicts progression to AIDS.

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            The pig as a model for human nutrition.

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              Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention.

              Although the balance of recent evidence supports the efficacy of antiretroviral (ARV)-based pre-exposure prophylaxis (PrEP) against HIV-1 infection, recent negative trial results are perplexing. Of seven trials with available HIV endpoints, three different products have been tested: tenofovir 1% vaginal gel, oral tenofovir disoproxil fumarate (TDF) tablets, and TDF/emtricitabine tablets. Six of these trials were conducted exclusively in sub-Saharan Africa; all found the products to be well tolerated, and four demonstrated effectiveness. Furthermore, the HIV Prevention Trial Network (HPTN) 052 trial recently confirmed that antiretroviral treatment leads to 96% reduction in transmission to HIV-negative partners in HIV-serodiscordant couples. These results, along with human and animal data, provide substantial evidence for the efficacy of antiretroviral-based HIV prevention. Yet assessment of oral TDF/emtricitabine in the FEM-PrEP study and of oral and vaginal tenofovir in the Microbicide Trial Network (MTN)-003 trial (VOICE) was stopped for futility. How do we make sense of these discrepant results? We believe that adherence is a key factor, although it cannot be the only factor. Expanding upon a recent editorial in the Lancet, we discuss the impact of suboptimal product adherence on PrEP efficacy in the context of variable drug concentration at the exposure site, integrity of the vaginal epithelium, and the role of acute infection.
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                Author and article information

                Contributors
                rlanger@mit.edu
                ctraverso@bwh.harvard.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                9 January 2018
                9 January 2018
                2018
                : 9
                : 2
                Affiliations
                [1 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, , Massachusetts Institute of Technology, ; Cambridge, MA 02139 USA
                [2 ]ISNI 0000 0004 1765 5089, GRID grid.15399.37, Département Biosciences, , Institut National des Sciences Appliquées de Lyon, ; 20 Avenue Albert Einstein, Villeurbanne, France 69100
                [3 ]ISNI 000000041936754X, GRID grid.38142.3c, Program for Evolutionary Dynamics, , Harvard University, ; Cambridge, Massachusetts 02138 USA
                [4 ]Institute for Disease Modeling, Bellevue, WA 98005 USA
                [5 ]ISNI 000000041936754X, GRID grid.38142.3c, Division of Gastroenterology Brigham and Women’s Hospital, , Harvard Medical School, ; Boston, MA 02115 USA
                [6 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Department of Mechanical Engineering, , Massachusetts Institute of Technology, ; Cambridge, MA 02139 USA
                [7 ]Lyndra Inc, Watertown, MA 02472 USA
                [8 ]Biomatics Capital, 1107 1st Avenue, Apartment 1305, Seattle, WA 98101 USA
                [9 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Media Lab, , Massachusetts Institute of Technology, ; Cambridge, MA 02139 USA
                [10 ]ISNI 0000 0001 2341 2786, GRID grid.116068.8, Institute for Medical Engineering and Science, , Massachusetts Institute of Technology, ; Cambridge, MA 02139 USA
                Author information
                http://orcid.org/0000-0002-3779-0363
                http://orcid.org/0000-0002-6583-3623
                http://orcid.org/0000-0002-2973-8530
                http://orcid.org/0000-0002-1278-3765
                http://orcid.org/0000-0001-5489-0908
                http://orcid.org/0000-0001-7851-4077
                Article
                2294
                10.1038/s41467-017-02294-6
                5760734
                29317618
                5c84a8b3-c699-47f8-9d47-a9116ecb684a
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 8 April 2017
                : 16 November 2017
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