Can a Topical Microbicide Prevent Rectal HIV Transmission?

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 [3]. 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 [4]. 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. A third key study by Martin Cranage and colleagues is published in this issue of PLoS Medicine [5]. The researchers investigated whether rectal simian immunodeficiency virus (SIV) transmission in macaques could be prevented by the topical pre-exposure application of tenofovir gel. Rectal SIV or HIV challenge bears a much higher transmission probability than vaginal challenge. With some caveats, as discussed further below, successful prevention of rectal transmission is therefore likely to have a better predictive value for human trials than vaginal challenge models. Moreover, anal intercourse in heterosexual populations has been underestimated in the past, and means to prevent rectal HIV transmission are thus urgently needed for both women and men who have unprotected anal intercourse.