Pharmacokinetics and efficacy of topical inserts containing tenofovir alafenamide fumarate and elvitegravir administered rectally in macaques

Abstract

Background: Topical on-demand forms for HIV pre-exposure prophylaxis (PrEP) may be a desirable alternative for people that prefer not to use daily PrEP. CONRAD has developed inserts containing tenofovir alafenamide (TAF) and elvitegravir (EVG) for on-demand vaginal or rectal pericoital use. We assessed the pharmacokinetics (PK) and pre-exposure efficacy of rectally applied TAF/EVG inserts in macaques.

Methods: PK was assessed in 12 pigtailed macaques. Tenofovir (TFV) and EVG levels were assayed in rectal biopsies and secretions, and tenofovir-diphosphate (TFV-DP) levels in biopsies and peripheral blood mononuclear cells (PBMC). Drug biodistribution was evaluated in 10 animals at necropsy 4 h post-dosing. For efficacy assessments, one or two TAF/EVG inserts were administered to macaques (n = 6) 4 h before repeated rectal SHIV162p3 challenges.

Findings: One TAF/EVG insert resulted in rapid and high EVG and TFV-DP in rectal tissue 4 h after application. Adding a second insert led to a 10-fold increase in EVG and TFV-DP in rectal tissue. Efficacy of one and two TAF/EVG inserts were 72.6% (CI 24.5%-92.6%) and 93.1% (CI 73.3%-99.2%), respectively.

Interpretation: Although high TFV-DP and EVG levels were observed with one rectal TAF/EVG insert, it only conferred partial protection from rectal SHIV challenges. Adding a second insert led to an increase in TFV and EVG in rectal tissues resulting in higher (>90%) efficacy. These results highlight the high efficacy of TAF/EVG inserts as topical on-demand rectal PrEP, as well as the need for appropriate drug coverage in the deep rectum and colon to achieve high protection.

Funding: The work related to animal studies was funded by CDC intramural funds and an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002). The work related to the insert formulation was funded by U.S. PEPFAR through USAID under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. The findings and conclusions of this manuscript are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention (CDC), USAID, President's Emergency Plan for AIDS Relief (PEPFAR), Eastern Virginia Medical School (EVMS), or the US government.

Keywords: Elvitegravir; HIV pre-exposure prophylaxis; Macaque models; Tenofovir alafenamide; Topical PrEP.

Fig. 1

Pharmacokinetics of TFV, TFV-DP, and EVG in rectal fluids and tissue after one 20 mg TAF and 16 mg EVG insert dosing. TFV and EVG in rectal fluids (a, b) and tissue (c, d) and TFV-DP in rectal tissue (c right axis) normalised to the weight of the specimen. Each circle represents an individual animal. The horizontal line denotes the median. Values below LOQ (black dotted line for TFV and red dotted line for TFV-DP) were given a value of ½ of the LOQ.

Fig. 2

Pharmacokinetics of TFV, TFV-DP, and EVG in rectal fluids and tissue after two rectal 20 mg TAF and 16 mg EVG inserts. Median normalised drug levels (horizontal line) in rectal fluids (a, b) and tissue 4 h after dosing (c, d). Circles represent individual samples. Four fluid samples and three tissue samples per animal (n = 6) were plotted. Two rectal inserts were placed at 4 cm deep from the anal sphincter. Circles and squares represent samples after dosing without and with rectal cleansing, respectfully; red symbols are for TFV-DP (d right axis). Values below LOQ (black dotted line for TFV and red dotted line for TFV-DP) were given a value of ½ of the LOQ.

Fig. 3

Drug distribution in rectal compartment 4 h after TAF/EVG administration and rectal cleansing impact. Rectal biopsies were collected at 4 cm (R4), 8 cm (R8), 12 cm (R12), and 25 cm (c) from the anal sphincter 4 h after dosing. Drug concentrations (n = 8/animal) normalised to biopsy weight are plotted as scattered individual values. Rectal inserts were administered 4 cm deep from the anal sphincter either without prior rectal cleansing (1 insert: n = 2, blue or 2 inserts: n = 2, red) and after rectal cleansing (1 insert: n = 3, green or 2 inserts: purple). The second insert was placed at 8 cm from the anal opening. The horizontal line denotes the median. Zero values were given a value of half of the LOQ. Horizontal lines represent statistically significant differences of p < 0.05 (Wilcoxon rank-sum test).

Fig. 4

Rectal efficacy of TAF/EVG inserts administered 4h before SHIV exposure. Macaques received one or two weekly rectal inserts application and were exposed to SHIV162P3 at 4 h after dosing. The survival curve shows the cumulative percentage of uninfected macaques as a function of the number of weekly rectal SHIV162p3 exposures treated with one (a) and two (b) TAF/EVG inserts. Dashed black and solid black lines represent placebo controls (n = 7) and TAF/EVG insert (n = 6), respectively. Placebo controls were infected after a median of 2 exposures. TAF/EVG 1 insert animals were infected after a median of 4 exposures, and the calculated efficacy was 72.60%, with a 95% exact CI (24.47%, 92.66%); challenges were stopped after six weeks. TAF/EVG 2 inserts animals received 10 challenges. The calculated efficacy was 93.14%, with a 95% exact CI (73.26%, 99.21%). Animals in both arms were followed for an additional 5 weeks to monitor infection.