Two-dose emtricitabine/tenofovir alafenamide plus bictegravir prophylaxis protects macaques against SHIV infection

Abstract

Objectives Current prophylaxis options for people at risk for HIV infection include two US FDA-approved daily pre-exposure prophylaxis (PrEP) regimens and guidelines for a 2-1-1 event-driven course specifically for men who have sex with men. Despite this, PrEP use rates remain suboptimal, and additional PrEP options may help to improve uptake among diverse populations. Here, we evaluated protective efficacy of two-dose PrEP and two-dose postexposure prophylaxis (PEP) schedules with emtricitabine (FTC)/tenofovir alafenamide (TAF) with or without bictegravir (BIC) in an SHIV macaque model. Methods Macaques received one oral dose of 200 mg emtricitabine, 25 mg tenofovir alafenamide and 25-100 mg of bictegravir to establish pharmacokinetic profiles of each drug either in the plasma or the peripheral blood mononuclear cells. Protective efficacy of multiple two-dose PrEP and PEP schedules with FTC/TAF with or without bictegravir was then assessed in two repeat low-dose rectal SHIV challenge studies. Results The data revealed over 95% per-exposure risk reduction with FTC/TAF PrEP initiated 2 h before the exposure, but a loss of significant protection with treatment initiation postexposure. In contrast, FTC/TAF plus BIC offered complete protection as PrEP and greater than 80% per-exposure risk reduction with treatment initiation up to 24 h postexposure. Conclusions Together, these results demonstrate that two-dose schedules can protect macaques against SHIV acquisition and highlight the protective advantage of adding the integrase inhibitor bictegravir to the reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide as part of event-driven prophylaxis.

Safety and Tolerability of Once Daily Coformulated Bictegravir, Emtricitabine, and Tenofovir Alafenamide for Postexposure Prophylaxis After Sexual Exposure

“…[13][14][15] Simian retroviral challenge studies have found that a single pre-exposure and single postexposure dose of this combination was highly protective. 16 The current study found this regimen to be safe and well-tolerated with the best completion rates (over 90%) of any PEP regimen studied at our center. Although PEP-associated side effects of nausea/vomiting, diarrhea/loose stool, fatigue, and headache were occasionally noted, they were generally mild, and were less common than previously studied PEP regimens.…”

“…Given that 2 of the 3 drugs used in oral PrEP regimens are present in BIC/FTC/TAF, it is reasonable to presume that people who tolerate the 3-drug regimen could readily transition to the 2-drug regimen for chronic PrEP. Given that simian studies suggest that BIC/FTC/TAF was protective when given as event-driven PEP/PrEP (ie, one dose before and after a retroviral challenge), 16 it is also possible that this combination could become used as an on-demand PrEP regimen; but, this approach would require human studies.…”

“…[13][14][15] A simian retroviral challenge study found that animals who received one dose of BIC/FTC/TAF before and after exposure to simian immunodeficiency virus were highly protected from infection. 16 In a phase 1 trial, 20 participants took part in a 10-day monotherapy study comparing BIC to placebo with 4 participants assigned to one of four dosage groups (5 mg, 25 mg, 50 mg, and 100 mg) and 5 participants assigned to a placebo. 17 Participants in all 4 study arms experienced rapid and sustained declines in HIV plasma RNA.…”

Bictegravir/Emtricitabine/Tenofovir Alafenamide for HIV-1: What is the Hidden Potential of This Emerging Treatment?

“…29 Given the timing of HIV DNA integration after reverse transcription, it has been hypothesized that adding an INSTI to an NRTI regimen for 2-1-1 PrEP may increase the window of prevention. 30 This was explored in a SHIV macaque study of two-dose, event-driven therapy. 30 When administered 2 hours before and 24 hours after, emtricitabine/TAF (F/TAF) and bictegravir 25 mg prevented 100% (6/6) of SHIV seroconversion but this was similar to F/TAF alone (5/6, 83%, 95.2% per-exposure risk reduction).…”

The predictive value of macaque models of preexposure prophylaxis for HIV prevention

“…[ 34 ▪▪ ]. A second study with two oral doses of emtricitabine, tenofovir alafenamide and bictegravir found complete protection against rectal SHIV infection when the doses were administered 2 h before and 24 h post challenge, and 82%–90% efficacy when the two dose regimen was initiated within 24 h after exposure [ 35 ▪ ]. These two macaque studies document biological efficacy of a “before or after sex” HIV prevention pill that may better adapt to different needs among PrEP and PEP users.…”