Background:  Both Truvada and topical 1% vaginal tenofovir (TFV) have been shown to prevent HIV-1 infection. Here we assess the safety, acceptability, and pharmacokinetics of oral tenofovir (TDF) and rectal application of 1% vaginal TFV gel as well as their efficacy in suppressing ex vivo HIV infection of rectal biopsies.

Methods:  We enrolled 18 healthy subjects at 2 sites (14 men, 4 women; median age 44) who sequentially received:  a single dose of TDF (300 mg) (O), a single rectal dose (R) randomized to TFV or placebo (2:1 ratio), and 7 days’ rectal dosing (R7), also randomized. General and mucosal safety was monitored throughout. Product acceptability was assessed after R7. Ex vivo rectal biopsy infectibility and plasma drug concentrations were measured at 5 time points after O and R and once after R7.

Results:  All enrolled subjects completed the trial. No differences in grade 1 or 2 adverse events were seen between treatment arms. In 3 subjects, 8 grade 3 adverse events were reported; 6 of 8 events occurred during R7 in 2 subjects (TFV gel arm). No significant changes were seen in mucosal safety parameters except for decreases in tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1) secretion post R7 (TFV gel arm). Only 25% of subjects receiving TFV liked the gel vs 50% using placebo although 75% (TVF) and 67% (placebo) reported high likelihood of future use. Plasma TFV C_max and AUC were 23- and 30-fold higher during O (C_max at 2 hours) vs R (C_max at 0.5 hour; C_24h was detectable in 50%). Plasma TFV C_max was 25% lower and AUC 40% higher with R7 vs R (R7 C_max was 8 ng/mL at 0.5 hour; C_24h was detected in 50% of subjects). No significant HIV suppression was seen following O. A non-significant decline of p24 at 0.5 hour was seen with R (p = 0.12; effect size = 0.49). R7 showed significant suppression of infection from baseline (p = 0.02 effect size = 0.80).

Conclusions:  Rectal dosing with the vaginal formulation of 1% TFV was neither entirely safe nor fully acceptable, indicating the need for development of a rectal-specific formulation of TFV in future rectal microbicide studies. That 7-day rectal TFV use resulted in very significant inhibition of ex vivo HIV infection increases the likelihood that a rectal-specific formulation of TFV might inhibit rectal acquisition of HIV in vivo. In contrast, neither single oral (TDF) nor rectal (TFV) dosing significantly inhibited biopsy infection, suggesting a single pericoital use of these might not be an effective prevention strategy in reducing HIV transmission during anal intercourse.