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.

Figure 1.

Study-1: emtricitabine/tenofovir alafenamide (FTC/TAF) and FTC/TAF + 25 mg bictegravir (BIC) two-dose regimens are effective as PrEP, but not PEP in macaques. (a) Efficacy Study-1 design. Negative hour values represent timing of drug dosing before SHIV exposure, positive time values represent drug dosing post exposure. SHIV challenge is denoted in red at time = 0. Six placebo control animals were split into three subgroups (n = 2 each) dosed at: −2 and +24; +24 and +48; or +48 and +72 h relative to SHIV challenge (b) Percentage of protected animals following eight repeat challenge/drug dosing cycles and a 6 month follow-up as determined by undetectable plasma viral load qRT-PCR read-out. SHIV challenges are denoted by black arrows under the x-axis. FTC/TAF and FTC/TAF + 25 mg BIC protect or delay time to infection relative to placebo control as shown. Each of three dosing schedules is plotted against the same group of six placebo control animals, all evaluated in parallel. (c) Summary of the fraction of animals protected, the resulting hazard ratios with 95% CIs and the per-exposure risk reduction rates at the end of study. P value determined using Cox proportional hazard regression model. Statistically significant values below a two-sided alpha level of 0.05 are shown in bold.

Figure 2.

Study-2: emtricitabine/tenofovir alafenamide (FTC/TAF) + 100 mg bictegravir (BIC), but not FTC/TAF alone, is effective as PEP in macaques. (a) Efficacy Study-2 design. Negative hour values represent timing of drug dosing before SHIV exposure, positive time values represent drug dosing post exposure. SHIV challenge is denoted in red at time = 0. Six placebo control animals were split into three subgroups (n = 2 each) dosed at: +6 and +30; +24 and +48; or +48 and +72 h relative to SHIV challenge (b) Percentage of protected animals following eight repeat challenge/drug dosing cycles and a 6 month follow-up as determined by undetectable plasma viral load qRT-PCR read-out. SHIV challenges are denoted by black arrows under the x-axis. FTC/TAF + 100 mg BIC protects or delays time to infection relative to placebo control as shown. Each of four dosing schedules is plotted against the same group of six placebo control animals all evaluated in parallel. (c) Summary of the fraction of animals protected, the resulting hazard ratios with 95% CIs and the per-exposure risk reduction rates at the end of study. P value determined using Cox proportional hazard regression model. Statistically significant values below a two-sided alpha level of 0.05 are shown in bold.