Background:
On-demand and behaviorally congruent forms of HIV pre-exposure prophylaxis (PrEP) have long been requested by communities at risk of HIV, especially men who have sex with men (MSM). Previously in DREAM-01, we reported safety, acceptability, and pharmacokinetics/pharmacodynamics (PK/PD) of three single-dose tenofovir (TFV) rectal douche formulations in MSM and identified a lead formulation. Given that MSM report using multiple douches for cleanliness prior to receptive anal intercourse, DREAM-03 sought to report safety and PK/PD outcomes when using multiple TFV douches with and without water douches.
Methods:
TFV douche products that consisted of 660 mg TFV in 125 mL hypo-osmolar saline were tested in three sequences: (A) three TFV douches, (B) one TFV douche then two tap water douches, and (C) two tap water douches then one TFV douche. We collected blood over 168 hours post-dose and rectal swabs/tissue biopsies over 72 hours. TFV and TFV diphosphate (TFV-DP) concentrations were quantified using validated methods. Anti-HIV effect was evaluated using an ex vivo colonic explant HIV challenge method with biopsies collected over 6 hours post-dose. An HIV p24 assay was used to quantify viral replication. Results among different sequences were compared using Wilcoxon signed-rank tests.
Results:
Nine male participants were enrolled, with a median (range) age of 38 (29, 52) years and a median weight of 77 (64, 113) kg. No grade >2 study related adverse events were reported. Plasma TFV concentrations at 4 and 6 hours were significantly higher (4.9- and 6.5-fold, respectively) in sequence A than those in sequence B (Figure 1A). A trend of higher TFV-DP concentrations in rectal mucosal mononuclear cells (MMCs) at 24 and 72 hours in sequences A (12.0- and 3.5-fold, respectively) and C (5.1- and 4.2-fold, respectively) than those in sequence B were also observed (Figure 1B). Compared to pre-drug baseline, HIV replication after ex vivo HIV challenge demonstrated a concentration-response relationship with 2.8 log, 2.2 log10, and 2.2 log10 maximal effects for sequences A, B, and C, respectively.
Conclusions:
Our result demonstrates that administering three TFV rectal douches are well tolerated. In addition, using non-medicated douches after a TFV douche may likely reduce both systemic and local TFV exposures, and may subsequently compromise anti-HIV effect of the TFV douche. Our study suggests that after non-medicated douches, a TFV douche should be used to provide better protection against HIV.
