Extended Postexposure Protection Against Vaginal Simian/Human Immunodeficiency Virus Infection With Tenofovir Alafenamide Fumarate/Elvitegravir Inserts in Macaques

Abstract

Vaginal inserts that can be used on demand before or after sex may be a desirable human immunodeficiency virus (HIV) prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF, 20 mg) and elvitegravir (EVG, 16 mg) were highly protective against repeated simian/human immunodeficiency virus (SHIV) vaginal exposures when administered to macaques 4 hours before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8 hours or 24 hours after exposure maintains high efficacy (94.4% and 77.2%, respectively). These data extend the protective window by TAF/EVG inserts and inform their clinical development for on-demand prophylaxis in women.

Keywords: HIV preexposure and postexposure prophylaxis; elvitegravir; macaque models; tenofovir alafenamide; topical PrEP and PEP.

Figure 1.

Vaginal efficacy of tenofovir alafenamide fumarate/elvitegravir (TAF/EVG) inserts administered 8 or 24 h after simian/human immunodeficiency virus (SHIV) exposure. A, Schematic representation of studies. Red and inverted blue triangles represent virus challenges and insert applications, respectively. One TAF/EVG insert was applied 8 or 24 h after vaginal exposure with low-dose SHIV162p3 inoculum. B, Kaplan–Meier survival plot. The survival plot shows the cumulative percentage of uninfected macaques as a function of the number of weekly vaginal SHIV162p3 exposures. The dotted black line represents cumulative placebo controls (n = 9). The red solid and dashed lines represent TAF/EVG insert (n = 6) applied 8 or 24 h after virus exposure, respectively. Placebo controls were infected after a median of 3 exposures. At 8 and 24 h postexposure prophylaxis (PEP), the calculated efficacy was 94.41% (95% exact confidence interval [CI], 57.03%–99.27%) and 77.23% (95% exact CI, 20.00%–93.52%), respectively. Animals in both arms were followed for an additional 8 weeks to monitor for late infections. C, Plasma viral load of SHIV-infected animals. Individual infected animals from real-time and historical placebo controls (n = 8, dotted black lines), and 8 h (n = 1) and 24 h (n = 3) TAF/EVG inserts (red lines) aligned to the first day when viral RNA was detected (day 0). The median for all placebo and treated animals is shown with bolded black and red lines, respectively. Values below the limit of quantification (LOQ) were given a value of one-half the LOQ (LOQ = 50 copies/mL).

Figure 2.

The impact of repeated vaginal dosing on tenofovir-diphosphate (TFV-DP) levels at the time of virus exposure. A, Schematic representation of terminal pharmacokinetic study. Blue triangles and black arrows with circles represent the insert application and the time of the biopsy collection (7 d after the insert application), respectively. The second week’s insert application took place 24 h after biopsy collection. B, Levels in individual biopsies collected from 3 animals (open circles) were plotted. Filled circles represented the mean for each animal, and the lines depict the difference between 1 tenofovir alafenamide fumarate/elvitegravir (TAF/EVG) dose and 4 weekly doses. The animals are color-coded: FJ90 is green, A12W026 is blue, and Z14276 is red. Medians of 3 animals for 1 and 4 doses are depicted with horizontal black lines. Values below the limit of quantification (LOQ; black dotted line) were given a value of one-half the LOQ (LOQ was 10 fmol/mg of tissue).