Date Published: August 5, 2008
Publisher: Public Library of Science
Author(s): Florian Hladik, Charlene S Dezzutti
Abstract: Florian Hladik and Charlene Dezzutti discuss a macaque study of whether rectal simian immunodeficiency virus transmission can be prevented by topical pre-exposure application of tenofovir gel.
Partial Text: Animal models are critical tools for the preclinical evaluation of drugs. Yet in the HIV field, the value of such models for predicting the success of preventive drug and vaccination strategies in humans has been disappointing. For example, animal models were unable to predict the failure of vaginal microbicides in large clinical trials in humans [1,2]. However, two recently published studies have provided encouraging results. Using a repeat, low-dose exposure macaque model, Walid Heneine and colleagues found that systemic pre-exposure prophylaxis (PrEP), using a combination of the nucleoside analogue reverse transcriptase inhibitors emtricitabine and tenofovir, protected macaques against rectal challenge with simian HIV . Most prior macaque studies used single high-dose virus challenges, which are less representative of viral exposure in humans. Another study by J. Victor Garcia and colleagues introduced an improved mouse model of vaginal HIV transmission . Mice engineered to stably exhibit extensive infiltration of organs and tissues, including the female reproductive tract, with a broad range of human blood cells were protected from intravaginal HIV infection by PrEP with emtricitabine/tenofovir. This mouse model opened the way for larger-scale comparative assessments in vivo, which is impossible in macaques due to the prohibitively high costs.
Cranage and colleagues examined systemic infections of macaques after high-dose rectal SIV challenge, comparing animals that received 1% tenofovir gel in the rectum up to two hours before viral challenge to animals that received placebo gel or remained untreated. Six of nine macaques given tenofovir per rectum were completely protected from infection, and another two animals had either persistently low viral loads or markedly delayed onset of viremia. In contrast, all untreated macaques and three out of the four macaques that were given placebo gel became infected, exhibiting early viremia and higher viral loads. Three additional macaques received tenofovir gel per rectum two hours after virus challenge, and two of these became infected.
This is the first study showing that the topical application of a microbicide, tenofovir gel, to the rectum protects against a high-dose rectal challenge with SIV. In conjunction with the data in the paper on tenofovir pharmacokinetics and the induction of systemic anti-HIV cellular immunity by the viral challenge , the work will be informative for human microbicide trials.
Before moving topical tenofovir per rectum into a larger clinical trial in humans, the current study should be extended to two repeat-exposure modalities. First, a multiple tenofovir application/multiple virus challenge design will determine if repeated applications of the topical tenofovir formulation have a negative effect on the mucosa over time that in turn compromises the protective efficacy. Second, the interesting finding that viral exposure led to systemic HIV-specific T cell immunity in most of the protected animals in the current study warrants investigation of the biological significance of this observation. In theory, these responses may be either beneficial, because they contribute to resistance to infection, or detrimental, because they signify T cell activation and thus a higher susceptibility of target cells in the mucosa. To help clarify if the emergence of these responses is cause for optimism or concern, a set of animals who have developed HIV-specific T cell immunity should be rechallenged with SIV in the absence of microbicide protection. Another lesson from this observation is that HIV-specific T cell responses should be evaluated in ongoing human microbicide trials.