Background: Systemic levels of tenofovir (Gilead Sciences, Inc.) in macaques were previously shown to be effective for preventing SIV transmission by a single challenge with very high viral titers. In this study, Rhesus macaques (Macaca mulatta) were subjected to weekly rectal inoculations with more physiologic levels of SHIV that approximated HIV-1 levels found in human semen during an acute infection.

Methods:  Twelve male Chinese rhesus macaques were used with four animals in each study arm: 1) control arm- no TDF treatment; 2) daily arm- animals received TDF daily; 3) weekly arm- animals received TDF once weekly.  Animals in all study arms received once-weekly rectal inoculations with 3.8 X 10⁵ virus particles (10 TCID₅₀) of CCR5 using SHIV_SF162P3.  Animals in the daily and weekly treatment arms were given TDF (22 mg/Kg) orally, with food, 2 hours prior to rectal inoculation with SHIV_SF162P3. Tenofovir levels were measured from blood collected 2 hours after drug treatment. Cell-free plasma virus load was used as a marker for systemic infection. TDF treatment for animals in the daily and weekly arms was continued post-infection to monitor for emergence of the K65R mutation.

Results:  In the control group, 2 of 4 animals became infected after 1 inoculation each; the third and fourth animals became infected after 2 and 11 inoculations, respectively. In the daily arm, 2 of 4 animals were infected after 6 inoculations each; the third and fourth animals became infected after 9 and 14 inoculations, respectively.  In the weekly arm, 2 of 4 animals became infected after 6 inoculations each; the third and fourth animals became infected after 8 and 11 inoculations, respectively.  TDF treatment increased the median time to infection in the daily and weekly arms (7.5 weeks and 7 weeks, respectively) compared to the control arm (1.5 weeks); however in a survival analysis there was no statistical difference between the treated and control arms at 14 weeks (exact log-rank test p= 0.315; asymptotic likelihood ratio test p= 0.222). No K65R resistance mutation had developed through 16 weeks of the study. Plasma levels of tenofovir were found to be comparable to levels in humans receiving 300 mg.

Conclusions: This is the first application of a repeat-rectal exposure macaque-model to evaluate chemoprophylaxis as a method of preventing retroviral infection.  In this study, chemoprophylaxis with oral TDF delayed, but ultimately did not prevent infection via rectal exposure with virus levels similar to levels in human semen during an acute infection.

Keywords: Chemoprophylaxis; tenofovir; rhesus macaques