Research Article: Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir

Date Published: February 5, 2008

Publisher: Public Library of Science

Author(s): 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, Andrew Carr

Abstract: BackgroundIn 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 FindingsWe 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.ConclusionsThis 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.

Partial Text: With an estimated 33.2 million people worldwide living with HIV at the end of 2007 and an estimated 2.5 million new infections in 2007 acquired mostly through sex, HIV/AIDS continues to be a major global health challenge [1]. Currently, no vaccine is available to prevent HIV, and it is unlikely that one will be developed soon. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs is gaining considerable attention as a possible biomedical intervention strategy to prevent sexual transmission of HIV [2–5]. PrEP is a proven concept for other infectious diseases like malaria. Mathematical models estimate that over the next 10 y, an effective PrEP program could prevent 2.7 to 3.2 million new HIV-1 infections in sub-Saharan Africa [6]. This potentially significant public health benefit requires a very high PrEP efficacy and might be lost or substantially reduced with a PrEP efficacy of <50%. Therefore, identifying highly effective PrEP modalities is critical. In sexual transmission, HIV first replicates at a low level at the mucosal point of entry in the new host [7,8]. Effective PrEP can exploit this brief period of virus vulnerability by blocking HIV from establishing itself as a persistent infection. In this study, we investigated the relationship between PrEP antiviral activity and protection by using a repeat-exposure macaque model that closely resembles human transmission. At dosing equivalent to that used in humans, we found that daily FTC was partially protective, and that the addition of TDF increased effectiveness. We also show that subcutaneous FTC and high-dose tenofovir completely blocked rectal transmission. These findings show that full protection against repeated exposures by daily PrEP is possible in a primate model, and that PrEP effectiveness correlates with increases in antiviral activity. Source: http://doi.org/10.1371/journal.pmed.0050028

 

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