Hypo-osmolar formulation of TFV enema promotes uptake and metabolism of TFV in tissues and leading to prevention of SHIV/SIV infection [PublishAheadOfPrint]

Oral PrEP has been approved for prophylaxis of HIV-1 transmission, but is associated with high costs and issues of adherence. Protection from anal transmission of HIV using topical microbicides using methods congruent with sexual behavior offers the promise of improved adherence. We compared the PK and ex vivo efficacy of iso-osmolar (IOsm) and hypo-osmolar (HOsm) rectal enema formulations of tenofovir (TFV) in rhesus macaques. Single-dose PK of IOsm or HOsm high (5.28mg/mL) and low (1.76mg/mL) dose formulations of TFV enemas were evaluated for systemic uptake in blood, colorectal biopsies and rectal CD4+ T cells. Markedly higher TFV concentrations were observed in plasma and tissues after administration of the HOsm high dose formulation than all others tested. TFV and TFV diphosphate (TFV-DP) concentrations in tissue correlated for the HOsm high dose formulation, demonstrating rapid uptake and transformation of TFV to TFV-DP in tissues. TFV-DP in tissues collected at 1 and 24 hours were 7x and 5x higher, respectively (p<0.01) compared to the IOsm formulation. HOsm high dose formulation was prevented infection in ex vivo challenges of rectal tissues collected at 1, 24 and 72 hours after the intrarectal dosing, whereas the same TFV dose formulated as IOsm enema was less effective.

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