In spite of the PrEP with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) rollout, the rate of new HIV infections remains a major hurdle. In the US alone, the rate of new infections has shifted to predominantly men having sex with men in rural settings where access to PrEP can be an issue, in addition to cost and the need for adherence. As an alternative, we have developed an on demand PrEP approach using TFV-based hypo-osmolar (HOsm) rectal douches that are congruent with sexual behavior. Using stringent intrarectal repeated exposures of macaques to SHIV, this approach has delivered significantly better protective efficacy from virus acquisition compared to oral daily TDF and TDF/FTC PrEP. We therefore attempted to delineate the parameters that may dictate such improved efficacy and tested the safety of repeated TFV douching.
Sodium based HOsm intrarectal douches were compared to oral daily PrEP for their ability to promote uptake of TFV into the tissue and circulation.
Analysis of HOsm formulation of TFV douche delivery demonstrated the presence of >14,000 fmol/mg TFV-DP at 3 hours 2500 fmol/mg TFV-DP in rectal tissues at 24 h post rectal douching, markedly higher than the ~200 fmol/mg steady state achieved by daily oral PrEP. TFV-DP levels in all other tissues analyzed including colonic lymph nodes draining the rectal mucosa were considerably lower, between 10-30 fmol/mg irrespective of anatomical location. Of note, while single oral TDF and HOsm rectal TDF achieved the same peak of plasma TFV, general AUC were higher for the oral delivered TDF. Rapidly repeated HOsm rectal douching (x5) using 30 vs 60 ml did not cause any detectable tissue or systemic toxicity. The single vs repeated HOsm rectal douching achieved similar TFV and TFV-DP levels in colorectal tissues, but plasma TFV levels were significantly higher for the repeated 60 ml dosing. Gel and bicarbonate formulations of rectal TDF douching did not markedly improve the pharmacokinetics of TFV or TFV-DP in tissues.
TFV HOsm douching showed high protection efficacy and appeared well tolerated even after multiple administrations within 30 minutes. The most salient parameter potentially associated with protection from rectal infection appeared to be the considerably higher levels of TFV-DP at the portal of entry but not in distal lymphoid tissues, suggesting that drug levels at that barrier are critical for preventing mucosal virus acquisition.