A phase I study to assess safety, pharmacokinetics and pharmacodynamics of a topical multipurpose prevention insert containing tenofovir alafenamide fumarate and elvitegravir dosed vaginally

BACKGROUND: A discreet, on-demand, vaginal or rectal, pre- or post-exposure prophylaxis product is unique and fills an important gap in human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV-2) multipurpose prevention. We describe the safety, acceptability and multi-compartmental pharmacokinetics (PK) and pharmacodynamics (PD) after healthy women used a single vaginal insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG).
METHODS: This was a Phase I, open-label, study. Women (n=16) self-administered one TAF (20mg)/EVG (16mg) insert vaginally in the clinic and were randomized (1:1) into one of two sample collection time groups (4 and 48 hours versus 24 and 72 hours). All women were sampled 7 days post dosing. We assessed safety by treatment emergent adverse events. We measured EVG, TAF and tenofovir (TFV) concentrations in plasma, vaginal fluid and tissue and TFV-diphosphate (TFV-DP) in vaginal tissue. PD was modeled ex vivo by quantifying the change in inhibitory activity of vaginal fluid and vaginal tissue against HIV and HSV-2 after treatment, compared to baseline.
RESULTS: The TAF/EVG insert was safe, well tolerated and acceptable following a single vaginal dose. We measured high cervicovaginal fluid TFV, with mean and median concentrations exceeding 200,000 ng/mL for up to 24 hours post dosing (median 340,854 IQR (232,508, 474,736 ng/mL) and exceeding 1,000 ng/mL for up to 7 days post dosing. All participants had vaginal tissue EVG concentrations of > 1000 ng/g at 4 and 24 hours post dosing. TFV-DP tissue concentrations exceeded 1,000 fmol/mg by 24 and 72 hours post dosing in 75% of participants. Vaginal fluid inhibition of HIV and HSV-2 ex vivo was significantly (p<0.05) increased from baseline and was similarly high at 4 and 24 hours post dosing. Consistent with high tissue TFV-DP concentrations, p24 antigen production from ectocervical tissues infected ex vivo with HIV was significantly (p<0.05) decreased from baseline at 4 hours post dosing.
CONCLUSIONS: A single vaginal dose of TAF/EVG topical insert was safe, acceptable and effective in preventing HIV-1 and HSV-2 infection ex vivo in this first-in-woman clinical study. PK data support an extended window of high mucosal exposure.