Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaquesResearch in context
Summary: Background: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharm...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422005436 |
| _version_ | 1828183358144774144 |
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| author | Charles W. Dobard M. Melissa Peet Kenji Nishiura Angela Holder Chuong Dinh James Mitchell George Khalil Yi Pan Onkar N. Singh Timothy J. McCormick Vivek Agrahari Pardeep Gupta Sriramakamal Jonnalagadda Walid Heneine Meredith R. Clark J. Gerardo García-Lerma Gustavo F. Doncel |
| author_facet | Charles W. Dobard M. Melissa Peet Kenji Nishiura Angela Holder Chuong Dinh James Mitchell George Khalil Yi Pan Onkar N. Singh Timothy J. McCormick Vivek Agrahari Pardeep Gupta Sriramakamal Jonnalagadda Walid Heneine Meredith R. Clark J. Gerardo García-Lerma Gustavo F. Doncel |
| author_sort | Charles W. Dobard |
| collection | DOAJ |
| description | Summary: Background: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. Methods: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). Findings: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%–98.8%) and 100% (95% CI = undefined), respectively. Interpretation: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. Funding: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. |
| first_indexed | 2024-04-12T06:31:20Z |
| format | Article |
| id | doaj.art-55d8031cbca74a5682878f9dfe8e5255 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-12T06:31:20Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-55d8031cbca74a5682878f9dfe8e52552022-12-22T03:44:00ZengElsevierEBioMedicine2352-39642022-12-0186104361Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaquesResearch in contextCharles W. Dobard0M. Melissa Peet1Kenji Nishiura2Angela Holder3Chuong Dinh4James Mitchell5George Khalil6Yi Pan7Onkar N. Singh8Timothy J. McCormick9Vivek Agrahari10Pardeep Gupta11Sriramakamal Jonnalagadda12Walid Heneine13Meredith R. Clark14J. Gerardo García-Lerma15Gustavo F. Doncel16Laboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USACONRAD, Eastern Virginia Medical School (EVMS), Norfolk, VA, USALaboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USALaboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USALaboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USALaboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USAQuantitative Sciences and Data Management Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USAQuantitative Sciences and Data Management Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USACONRAD, Eastern Virginia Medical School (EVMS), Norfolk, VA, USACONRAD, Eastern Virginia Medical School (EVMS), Norfolk, VA, USACONRAD, Eastern Virginia Medical School (EVMS), Norfolk, VA, USAUniversity of the Sciences, Philadelphia, PA, USAUniversity of the Sciences, Philadelphia, PA, USALaboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USACONRAD, Eastern Virginia Medical School (EVMS), Norfolk, VA, USALaboratory Branch, Division of HIV Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA; Corresponding author. 1600 Clifton Road, Atlanta, GA 30329, USA.CONRAD, Eastern Virginia Medical School (EVMS), Norfolk, VA, USA; Corresponding author. 1911 North Fort Myer Drive, Suite 900, Arlington, VA 22209, USA.Summary: Background: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. Methods: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). Findings: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%–98.8%) and 100% (95% CI = undefined), respectively. Interpretation: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. Funding: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School.http://www.sciencedirect.com/science/article/pii/S2352396422005436Vaginal insertsTenofovir alafenamideElvitegravirOn-demand PrEP and PEP |
| spellingShingle | Charles W. Dobard M. Melissa Peet Kenji Nishiura Angela Holder Chuong Dinh James Mitchell George Khalil Yi Pan Onkar N. Singh Timothy J. McCormick Vivek Agrahari Pardeep Gupta Sriramakamal Jonnalagadda Walid Heneine Meredith R. Clark J. Gerardo García-Lerma Gustavo F. Doncel Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaquesResearch in context EBioMedicine Vaginal inserts Tenofovir alafenamide Elvitegravir On-demand PrEP and PEP |
| title | Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaquesResearch in context |
| title_full | Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaquesResearch in context |
| title_fullStr | Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaquesResearch in context |
| title_full_unstemmed | Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaquesResearch in context |
| title_short | Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaquesResearch in context |
| title_sort | single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre and post exposure protection against vaginal shiv infection in macaquesresearch in context |
| topic | Vaginal inserts Tenofovir alafenamide Elvitegravir On-demand PrEP and PEP |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422005436 |
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