Randomized, placebo-controlled trial of safety, pharmacokinetics, and pharmacodynamics of 90-day intravaginal rings (IVRs) releasing tenofovir (TFV) with and without levonorgestrel (LNG) among women in Western Kenya


BACKGROUND: Globally, young women face parallel epidemics of HIV infection and unintended pregnancy. Protection from both requires safe and effective prevention tools.
METHODS: Healthy women ages 18-34 years, not pregnant, HIV-seronegative, HBsAg-negative, not using hormonal contraception, of reproductive potential, and at low risk for HIV were randomized 2:2:1 to continuous use of a TFV/LNG, TFV or placebo IVR. We assessed genital and systemic safety, TFV concentrations in both plasma and cervicovaginal fluid (CVF) and LNG levels in serum using mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through anti-HIV and anti-HSV activity in CVF ex vivo, and LNG PD using cervical mucus quality markers and serum progesterone measurement for ovulation inhibition.
RESULTS: Among 312 women screened, 27 were randomized to use IVRs: TFV/LNG (n=11); TFV alone (n=11); and placebo (n=5). Most screen fails were due to vaginal infections. Median (IQR) days of ring use was 68 (36-90). Women reported more intermittent bleeding events with TFV/LNG IVR use than in the other two arms, but otherwise adverse events (AE) were distributed similarly among arms. There were two non-product related AEs graded >2. No visible genital lesions were observed.. Steady state geometric mean concentration (ssGMC) vaginal TFV amount was comparable in the TFV/LNG arm (44.0μg/swab (95% CI (31.2, 62.0)) and the TFV alone arm (30.3μg/swab (95% CI (18.1, 50.7)), p=0.25. Plasma TFV ssGMC was <10ng/mL for both TFV rings. In vitro, CVF anti-HIV activity showed increased HIV inhibition over baseline following IVR use, from a median of -7% to 84% in TFV/LNG, 15% to 89% in TFV alone, and '27% (increased ex vivo infection) to '20% in placebo participants. LNG ssGMC was 240pg/mL (95% CI 170, 340) with rapid decline after removal to 90pg/mL (95% CI 60, 120) within 24 hours. Following 15 days of IVR use, progesterone levels in luteal phase indicated anovulation (<3ng/ml) more frequently using TFV/LNG (63.6%) compared to TFV (18.2%) and placebo (0.0%).
CONCLUSIONS: TFV/LNG and TFV alone IVRs were shown to be safe when used by African women. Pharmacokinetic characteristics and markers of protection against HIV-1 and pregnancy suggest the potential for clinical efficacy of these IVRs.