Randomized, placebo controlled phase I trial of the safety, pharmacokinetics, pharmacodynamics and acceptability of a 90 day tenofovir plus levonorgestrel vaginal ring used continuously or cyclically in women: The CONRAD 138 study

Abstract

Multipurpose prevention technologies (MPTs), which prevent sexually transmitted infection(s) and unintended pregnancy, are highly desirable to women. In this randomized, placebo-controlled, phase I study, women used a placebo or tenofovir (TFV) and levonorgestrel (LNG) intravaginal ring (IVR), either continuously or cyclically (three, 28-day cycles with a 3 day interruption in between each cycle), for 90 days. Sixty-eight women were screened; 47 were randomized to 4 arms: TFV/LNG or placebo IVRs used continuously or cyclically (4:4:1:1). Safety was assessed by adverse events and changes from baseline in mucosal histology and immune mediators. TFV concentrations were evaluated in multiple compartments. LNG concentration was determined in serum. Modeled TFV pharmacodynamic antiviral activity was evaluated in vaginal and rectal fluids and cervicovaginal tissue ex vivo. LNG pharmacodynamics was assessed with cervical mucus quality and anovulation. All IVRs were safe with no serious adverse events nor significant changes in genital tract histology, immune cell density or secreted soluble proteins from baseline. Median vaginal fluid TFV concentrations were >500 ng/mg throughout 90d. TFV-diphosphate tissue concentrations exceeded 1,000 fmol/mg within 72hrs of IVR insertion. Mean serum LNG concentrations exceeded 200 pg/mL within 2h of TFV/LNG use, decreasing quickly after IVR removal. Vaginal fluid of women using TFV-containing IVRs had significantly greater inhibitory activity (87-98% versus 10% at baseline; p<0.01) against HIV replication in vitro. There was a >10-fold reduction in HIV p24 antigen production from ectocervical tissues after TFV/LNG exposure. TFV/LNG IVR users had significantly higher rates of anovulation, lower Insler scores and poorer/abnormal cervical mucus sperm penetration. Most TFV/LNG IVR users reported no change in menstrual cycles or fewer days of and/or lighter bleeding. All IVRs were safe. Active rings delivered high TFV concentrations locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. Trial registration: ClinicalTrials.gov #NCT03279120.

Fig 1. Disposition of participants.

Fig 2

a. Median (IQR) TFV (ng/mg) in vaginal fluid continuous dosing. b. Median (IQR) TFV (ng/mg) in vaginal fluid interrupted dosing. Black = IVR treatment, Green = post 3 day removal, Blue = end of treatment, Red = post IVR removal.

Fig 3

a. Median (IQR) tenofovir concentration (ng/mg) in vaginal tissue. b. Median (IQR) TFV-DP concentration (ng/mg) in vaginal tissue. Black = visit 5 (24, 48 or 72 hours post IVR insertion), Blue line = end of treatment; Red = post IVR removal.

Fig 4

a. Inhibition of HIV growth in vitro by vaginal fluids of TFV/LNG IVR users (continuous and cyclic dosing regimens combined) at baseline and 1 and 3 months after use. b. Correlation between [TFV] and Anti-HIV activity in CVF TFV/LNG IVRs.

Fig 5

a. Median (IQR) HSV2 DNA inhibition. b. Correlation HSV2 inhibition versus TFV in vaginal fluid (TFVLNG IVRs).

Fig 6. Serum LNG (pg/mL) in TFV/LNG continuous IVR Users (n = 18) and in TFV/LNG interrupted IVR users IVR users (n = 17).