Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir

J. Gerardo García-Lerma, Ron A. Otten, Shoukat H. Qari, Eddie Jackson, Mian Er Cong, Silvina Masciotra, Wei Luo, Caryn Kim, Debra R. Adams, Michael Monsour, Jonathan Lipscomb, Jeffrey A. Johnson, David Delinsky, Raymond F. Schinazi, Robert Janssen, Thomas M. Folks, Walid Heneine

Research output: Contribution to journalArticle

259 Citations (Scopus)

Abstract

Background: In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. Methods and Findings: We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. Conclusions: This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.

Original languageEnglish (US)
Pages (from-to)291-299
Number of pages9
JournalPLoS Medicine
Volume5
Issue number2
DOIs
StatePublished - Feb 2008
Externally publishedYes

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Tenofovir
Macaca
Drug therapy
Viruses
Pharmaceutical Preparations
Animals
AIDS Vaccines
Antiviral Agents
Macaca mulatta
Emtricitabine
Pre-Exposure Prophylaxis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

García-Lerma, J. G., Otten, R. A., Qari, S. H., Jackson, E., Cong, M. E., Masciotra, S., ... Heneine, W. (2008). Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Medicine, 5(2), 291-299. https://doi.org/10.1371/journal.pmed.0050028

Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. / García-Lerma, J. Gerardo; Otten, Ron A.; Qari, Shoukat H.; Jackson, Eddie; Cong, Mian Er; Masciotra, Silvina; Luo, Wei; Kim, Caryn; Adams, Debra R.; Monsour, Michael; Lipscomb, Jonathan; Johnson, Jeffrey A.; Delinsky, David; Schinazi, Raymond F.; Janssen, Robert; Folks, Thomas M.; Heneine, Walid.

In: PLoS Medicine, Vol. 5, No. 2, 02.2008, p. 291-299.

Research output: Contribution to journalArticle

García-Lerma, JG, Otten, RA, Qari, SH, Jackson, E, Cong, ME, Masciotra, S, Luo, W, Kim, C, Adams, DR, Monsour, M, Lipscomb, J, Johnson, JA, Delinsky, D, Schinazi, RF, Janssen, R, Folks, TM & Heneine, W 2008, 'Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir', PLoS Medicine, vol. 5, no. 2, pp. 291-299. https://doi.org/10.1371/journal.pmed.0050028
García-Lerma, J. Gerardo ; Otten, Ron A. ; Qari, Shoukat H. ; Jackson, Eddie ; Cong, Mian Er ; Masciotra, Silvina ; Luo, Wei ; Kim, Caryn ; Adams, Debra R. ; Monsour, Michael ; Lipscomb, Jonathan ; Johnson, Jeffrey A. ; Delinsky, David ; Schinazi, Raymond F. ; Janssen, Robert ; Folks, Thomas M. ; Heneine, Walid. / Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. In: PLoS Medicine. 2008 ; Vol. 5, No. 2. pp. 291-299.
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abstract = "Background: In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. Methods and Findings: We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. Conclusions: This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.",
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AU - García-Lerma, J. Gerardo

AU - Otten, Ron A.

AU - Qari, Shoukat H.

AU - Jackson, Eddie

AU - Cong, Mian Er

AU - Masciotra, Silvina

AU - Luo, Wei

AU - Kim, Caryn

AU - Adams, Debra R.

AU - Monsour, Michael

AU - Lipscomb, Jonathan

AU - Johnson, Jeffrey A.

AU - Delinsky, David

AU - Schinazi, Raymond F.

AU - Janssen, Robert

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AU - Heneine, Walid

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N2 - Background: In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission. Methods and Findings: We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected. Conclusions: This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.

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