A Randomized, Double-Blind Phase 1 Safety and Pharmacokinetic Study of Q-Griffithsin Douche Administered Rectally to HIV-1 Seronegative Adults (the PREVENT Study)

The availability of oral and long-acting injectable pre-exposure prophylaxis (PrEP) has transformed human immunodeficiency virus (HIV) prevention; however, some individuals may prefer behaviorally congruent, nonsystemic, on-demand rectal PrEP options that avoid chronic systemic exposure. The Q-Griffithsin (Q-GRFT) rectal douche is a novel, user-controlled PrEP candidate, containing a natural (red alga–derived), potent broad-spectrum antiviral lectin for pericoital rectal use. This first-in-human Phase 1 trial evaluated the safety, pharmacokinetics (PKs), pharmacodynamics (PDs), and acceptability of a single Q-GRFT rectal douche dose. Sixteen HIV-negative participants (eight female and eight male) with a history of recent receptive anal intercourse were enrolled in this randomized, double-blind study. Following single-dose administration, blood, rectal fluid, and rectal tissue samples were collected for safety, PK, and PD analyses using an ex vivo rectal explant HIV challenge model. Acceptability was measured using structured questionnaires. The Q-GRFT douche was safe with no Grade 3 or 4 adverse events or significant histological abnormalities. Acceptability was high at 93% of the study product. At 1 h postdose, geometric mean (range) Q-GRFT concentrations were 522.18 ng/mL (52.8–12,482.2) in rectal swab eluate and 6.85 µg (0.80–51.07) in rectal tissue, declining over 24 h. Q-GRFT was not detectable in plasma. Higher individual tissue drug levels correlated with reduced HIV infectivity in both rectal eluate ( p = 0.036) and tissue explant ( p = 0.003). In this first-in-human study, a single administration of Q-GRFT as a rectal douche demonstrated favorable safety, acceptability, and high local drug exposure without systemic absorption, supporting further evaluation as an on-demand, nonsystemic rectal PrEP strategy.