Preventive Efficacy of a Tenofovir Alafenamide Fumarate Nanofluidic Implant in SHIV-Challenged Nonhuman Primates

Fernanda P. Pons-Faudoa; Antons Sizovs; Kathryn A. Shelton; Zoha Momin; Jean A. Niles; Lane R. Bushman; Jiaqiong Xu; Corrine Ying Xuan Chua; Joan E. Nichols; Sandra Demaria; Michael M. Ittmann; Trevor Hawkins; James F. Rooney; Mark A. Marzinke; Jason T. Kimata; Peter L. Anderson; Pramod N. Nehete; Roberto C. Arduino; Mauro Ferrari; K. Jagannadha Sastry; Alessandro Grattoni

doi:10.1002/adtp.202000163

Preventive Efficacy of a Tenofovir Alafenamide Fumarate Nanofluidic Implant in SHIV-Challenged Nonhuman Primates

Fernanda P. Pons-Faudoa, Antons Sizovs, Kathryn A. Shelton, Zoha Momin, Jean A. Niles, Lane R. Bushman, Jiaqiong Xu, Corrine Ying Xuan Chua, Joan E. Nichols, Sandra Demaria, Michael M. Ittmann, Trevor Hawkins, James F. Rooney, Mark A. Marzinke, Jason T. Kimata, Peter L. Anderson, Pramod N. Nehete, Roberto C. Arduino, Mauro Ferrari, K. Jagannadha SastryAlessandro Grattoni

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing human immunodeficiency virus (HIV) transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here it is shown that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. It is demonstrated that sustained subcutaneous delivery through nTAF in rhesus macaques maintains tenofovir diphosphate concentration at a median of 390 fmol per 10⁶ peripheral blood mononuclear cells, nine times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal simian HIV_SF162P3 (SHIV_SF162P3) challenge, the nTAF cohort has a 62.50% reduction (95% CI: 1.72–85.69%; p = 0.068) in risk of infection per exposure compared to the control. This finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60% protective efficacy is observed in macaques, and clinically, 67% reduction in risk with 86% preventive efficacy in individuals with detectable drug in the plasma. Overall, this nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.

Original language	English (US)
Article number	2000163
Pages (from-to)	2000163
Number of pages	1
Journal	advanced therapeutics
Volume	4
Issue number	3
Early online date	Dec 16 2020
DOIs	https://doi.org/10.1002/adtp.202000163 https://doi.org/10.1002/adtp.202000163
State	Published - Mar 2021

Keywords

drug delivery
HIV pre-exposure prophylaxis
implantable devices
nanofluidics
tenofovir alafenamide

ASJC Scopus subject areas

Medicine (miscellaneous)
Pharmacology
Pharmaceutical Science
Genetics(clinical)
Biochemistry, medical
Pharmacology (medical)

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Pons-Faudoa, F. P., Sizovs, A., Shelton, K. A., Momin, Z., Niles, J. A., Bushman, L. R., Xu, J., Chua, C. Y. X., Nichols, J. E., Demaria, S., Ittmann, M. M., Hawkins, T., Rooney, J. F., Marzinke, M. A., Kimata, J. T., Anderson, P. L., Nehete, P. N., Arduino, R. C., Ferrari, M., ... Grattoni, A. (2021). Preventive Efficacy of a Tenofovir Alafenamide Fumarate Nanofluidic Implant in SHIV-Challenged Nonhuman Primates. advanced therapeutics, 4(3), 2000163. Article 2000163. https://doi.org/10.1002/adtp.202000163, https://doi.org/10.1002/adtp.202000163

Pons-Faudoa, FP, Sizovs, A, Shelton, KA, Momin, Z, Niles, JA, Bushman, LR, Xu, J , Chua, CYX , Nichols, JE, Demaria, S, Ittmann, MM, Hawkins, T, Rooney, JF, Marzinke, MA, Kimata, JT, Anderson, PL, Nehete, PN, Arduino, RC, Ferrari, M, Sastry, KJ & Grattoni, A 2021, 'Preventive Efficacy of a Tenofovir Alafenamide Fumarate Nanofluidic Implant in SHIV-Challenged Nonhuman Primates', advanced therapeutics, vol. 4, no. 3, 2000163, pp. 2000163. https://doi.org/10.1002/adtp.202000163, https://doi.org/10.1002/adtp.202000163

@article{67a4dc591f0846bbbc2a20d5553a34dc,

title = "Preventive Efficacy of a Tenofovir Alafenamide Fumarate Nanofluidic Implant in SHIV-Challenged Nonhuman Primates",

abstract = "Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing human immunodeficiency virus (HIV) transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here it is shown that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. It is demonstrated that sustained subcutaneous delivery through nTAF in rhesus macaques maintains tenofovir diphosphate concentration at a median of 390 fmol per 106 peripheral blood mononuclear cells, nine times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal simian HIVSF162P3 (SHIVSF162P3) challenge, the nTAF cohort has a 62.50% reduction (95% CI: 1.72–85.69%; p = 0.068) in risk of infection per exposure compared to the control. This finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60% protective efficacy is observed in macaques, and clinically, 67% reduction in risk with 86% preventive efficacy in individuals with detectable drug in the plasma. Overall, this nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.",

keywords = "drug delivery, HIV pre-exposure prophylaxis, implantable devices, nanofluidics, tenofovir alafenamide",

author = "Pons-Faudoa, {Fernanda P.} and Antons Sizovs and Shelton, {Kathryn A.} and Zoha Momin and Niles, {Jean A.} and Bushman, {Lane R.} and Jiaqiong Xu and Chua, {Corrine Ying Xuan} and Nichols, {Joan E.} and Sandra Demaria and Ittmann, {Michael M.} and Trevor Hawkins and Rooney, {James F.} and Marzinke, {Mark A.} and Kimata, {Jason T.} and Anderson, {Peter L.} and Nehete, {Pramod N.} and Arduino, {Roberto C.} and Mauro Ferrari and Sastry, {K. Jagannadha} and Alessandro Grattoni",

note = "Funding Information: The authors thank Dr. Andreana L. Rivera, Yuelan Ren, and Sandra Steptoe from the research pathology core of Houston Methodist Research Institute, Dr. Jianhua ?James? Gu from the electron microscopy core and Simone Capuani from the Houston Methodist Research Institute for implant design and rendering, Dixita Viswanath for help with tissue dissection, and Nicola Di Trani for obtaining FIB image. The authors also thank Jesus Paez-Mayorga and Dr. Dorothy Lewis for the useful discussions and Luke Segura, Elizabeth Lindemann and Dr. Greg Wilkerson from the Michale E. Keeling Center for Comparative medicine and Research at UTMDACC for support in animal studies, and Bharti Nehete for plasma and PBMC isolation and virus challenge preparation. TAF fumarate was provided by Gilead Sciences, Inc. Funding: This work was supported by funding from the National Institutes of Health National Institute of Allergy and Infectious Diseases (R01AI120749; A.G.) and Gilead Sciences (A.G.). The development of the nanochannel membrane used in the studies was funded by the National Institutes of Health National Institute of General Medical Sciences (R01GM127558; A.G.). F.P.P. receieved funding support from Tecnologico de Monterrey and Consejo Nacional de Ciencia y Tecnologia. Publisher Copyright: {\textcopyright} 2020 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH",

year = "2021",

month = mar,

doi = "10.1002/adtp.202000163",

language = "English (US)",

volume = "4",

pages = "2000163",

journal = "advanced therapeutics",

issn = "2366-3987",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "3",

}

TY - JOUR

T1 - Preventive Efficacy of a Tenofovir Alafenamide Fumarate Nanofluidic Implant in SHIV-Challenged Nonhuman Primates

AU - Pons-Faudoa, Fernanda P.

AU - Sizovs, Antons

AU - Shelton, Kathryn A.

AU - Momin, Zoha

AU - Niles, Jean A.

AU - Bushman, Lane R.

AU - Xu, Jiaqiong

AU - Chua, Corrine Ying Xuan

AU - Nichols, Joan E.

AU - Demaria, Sandra

AU - Ittmann, Michael M.

AU - Hawkins, Trevor

AU - Rooney, James F.

AU - Marzinke, Mark A.

AU - Kimata, Jason T.

AU - Anderson, Peter L.

AU - Nehete, Pramod N.

AU - Arduino, Roberto C.

AU - Ferrari, Mauro

AU - Sastry, K. Jagannadha

AU - Grattoni, Alessandro

N1 - Funding Information: The authors thank Dr. Andreana L. Rivera, Yuelan Ren, and Sandra Steptoe from the research pathology core of Houston Methodist Research Institute, Dr. Jianhua ?James? Gu from the electron microscopy core and Simone Capuani from the Houston Methodist Research Institute for implant design and rendering, Dixita Viswanath for help with tissue dissection, and Nicola Di Trani for obtaining FIB image. The authors also thank Jesus Paez-Mayorga and Dr. Dorothy Lewis for the useful discussions and Luke Segura, Elizabeth Lindemann and Dr. Greg Wilkerson from the Michale E. Keeling Center for Comparative medicine and Research at UTMDACC for support in animal studies, and Bharti Nehete for plasma and PBMC isolation and virus challenge preparation. TAF fumarate was provided by Gilead Sciences, Inc. Funding: This work was supported by funding from the National Institutes of Health National Institute of Allergy and Infectious Diseases (R01AI120749; A.G.) and Gilead Sciences (A.G.). The development of the nanochannel membrane used in the studies was funded by the National Institutes of Health National Institute of General Medical Sciences (R01GM127558; A.G.). F.P.P. receieved funding support from Tecnologico de Monterrey and Consejo Nacional de Ciencia y Tecnologia. Publisher Copyright: © 2020 The Authors. Advanced Therapeutics published by Wiley-VCH GmbH

PY - 2021/3

Y1 - 2021/3

N2 - Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing human immunodeficiency virus (HIV) transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here it is shown that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. It is demonstrated that sustained subcutaneous delivery through nTAF in rhesus macaques maintains tenofovir diphosphate concentration at a median of 390 fmol per 106 peripheral blood mononuclear cells, nine times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal simian HIVSF162P3 (SHIVSF162P3) challenge, the nTAF cohort has a 62.50% reduction (95% CI: 1.72–85.69%; p = 0.068) in risk of infection per exposure compared to the control. This finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60% protective efficacy is observed in macaques, and clinically, 67% reduction in risk with 86% preventive efficacy in individuals with detectable drug in the plasma. Overall, this nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.

AB - Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing human immunodeficiency virus (HIV) transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here it is shown that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. It is demonstrated that sustained subcutaneous delivery through nTAF in rhesus macaques maintains tenofovir diphosphate concentration at a median of 390 fmol per 106 peripheral blood mononuclear cells, nine times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal simian HIVSF162P3 (SHIVSF162P3) challenge, the nTAF cohort has a 62.50% reduction (95% CI: 1.72–85.69%; p = 0.068) in risk of infection per exposure compared to the control. This finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60% protective efficacy is observed in macaques, and clinically, 67% reduction in risk with 86% preventive efficacy in individuals with detectable drug in the plasma. Overall, this nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.

KW - drug delivery

KW - HIV pre-exposure prophylaxis

KW - implantable devices

KW - nanofluidics

KW - tenofovir alafenamide

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ER -

Preventive Efficacy of a Tenofovir Alafenamide Fumarate Nanofluidic Implant in SHIV-Challenged Nonhuman Primates

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