Single oral dose for HIV pre or post-exposure prophylaxis: user desirability and biological efficacy in macaques

Abstract

Background: Daily oral pre- or post-exposure prophylaxis (PrEP or PEP) is highly effective in preventing HIV infection. However, many people find it challenging to adhere to a daily oral regimen. Chemoprophylaxis with single oral doses of antiretroviral drugs taken before or after sex may better adapt to changing or unanticipated sexual practices and be a desirable alternative to daily PrEP or PEP. We investigated willingness to use a single oral pill before or after sex among men who have sex with men (MSM) and assessed the biological efficacy of a potent antiretroviral combination containing elvitegravir (EVG), emtricitabine (FTC), and tenofovir alafenamide (TAF).

Methods: Data on willingness to use single-dose PrEP or PEP were obtained from the 2017 cycle of the American Men's Internet Survey (AMIS), an annual online behavioral surveillance survey of MSM in the United States. Antiretroviral drug levels were measured in humans and macaques to define drug distribution in rectal tissue and identify clinically relevant doses for macaque modeling studies. The biological efficacy of a single dose of FTC/TAF/EVG as PrEP or PEP was investigated using a repeat-challenge macaque model of rectal HIV infection.

Findings: Through pharmacokinetic assessment in humans and macaques we found that EVG penetrates and concentrates in rectal tissues supporting its addition to FTC/TAF to boost and extend chemoprophylactic activity. Efficacy estimates for a single oral dose given to macaques 4h before or 2h after SHIV exposure was 91•7%[35•7%-98•9%] and 100%, respectively, compared to 80•1%[13•9%-95•4%] and 64•6%[-19•4%-89•5%] when single doses were given 6 and 24h post challenge, respectively. A two-dose regimen at 24h and 48h after exposure was also protective [77•1%[1•7%-94•7%].

Interpretation: Informed by user willingness, human and macaque pharmacokinetic data, and preclinical efficacy we show that single-dose prophylaxis before or after sex is a promising HIV prevention strategy. Carefully designed clinical trials are needed to determine if any of these strategies will be effective in humans.

Funding: Funded by CDC intramural funds, CDC contract HCVJCG2-2016-03948 (to CFK), and a grant from the MAC AIDS Fund and by the National Institutes of Health [P30AI050409] - the Emory Center for AIDS Research (to MZ and TS).

Keywords: HIV post-exposure prophylaxis; HIV pre-exposure prophylaxis; Integrase inhibitors; Macaque models.

Fig 1

Concentrations of TFV-DP and FTC-TP in PBMCs in macaques and humans. Macaques (n=4) received FTC (20 mg/kg), TAF (1•5 mg/k), EVG (30 mg/kg), and COBI (30 mg/kg) orally by gavage. Humans (n=7) received a single oral dose of co-formulated FTC/TAF/EVG/COBI tablet (200 mg of FTC, 10 mg of TAF, 150 mg EVG and 150 mg COBI). Values represent median (range) intracellular levels. Values below the LLOQ were assigned a value of 10 (TFV-DP) or 50 (FTC-TP) fmol /10⁶ cells or half of the LLOQ.

Fig 2

Drug concentrations in rectal tissues in macaques and humans. A) Concentrations of intracellular TFV-DP and FTC-TP. B) Concentrations of EVG, FTC, TFV. Macaques received a single oral dose of EVG (30 mg/kg), COBI (30 mg/kg), FTC (20 mg/kg) and TAF (1•5 mg/kg). HIV-negative men received a single oral dose of co-formulated FTC/TAF/EVG/COBI tablet (200 mg of FTC, 10 mg of TAF, 150 mg EVG and 150 mg COBI). Testing was done in 5 of the 7 participants. Horizontal red lines denote median concentrations observed in tissues at 24h. Undetectable levels were given an arbitrary value of 1000 fmols/g or 10 ng/g. None of the macaque to human comparisons reached statistical significance at the p<0•05 value. Median weight of macaque and human biopsies for intracellular drug level testing were 0•042 g and 0•020 g, respectively. Likewise, median weight of macaque and human biopsies for extracellular drug level testing were 0•037 g and 0•020 g, respectively.

Fig 3

Efficacy of single oral doses of FTC, TAF and boosted EVG as PrEP in macaques. A) Study design. B) Macaques received FTC, TAF and boosted EVG orally by gavage at the indicated time points relative to the time of rectal SHIV exposure. Survival curve shows the cumulative percentage of uninfected macaques as a function of the number of rectal SHIV exposures. Time to infection was delayed in animals receiving single-dose PrEP 4h or 24h before exposure (p=0•005 and p=0•027, respectively).

Fig 4

Efficacy of single oral doses of FTC, TAF and boosted EVG as PEP in macaques. A) Study design. B) Macaques received FTC, TAF and boosted EVG orally by gavage at the indicated time points relative to the time of rectal SHIV exposure. Survival curve shows the cumulative percentage of uninfected macaques as a function of the number of rectal SHIV exposures. Time to infection was delayed in animals receiving single-dose PEP 2h or 6h after exposure (p<0•001 and p=0•011, respectively. Time to infection was also delayed in animals receiving two PEP doses at 24 and 48h after exposure but not with a single +24h dose (p=0•013 and p=0•057, respectively).

Fig 5

Concentrations of TFV-DP in PBMCs at the time of SHIV challenge in PEP-treated animals. Animals received one or two doses of FTC/TAF/EVG/COBI at the indicated time after virus exposure. Values reflect median TFV-DP levels seen 2 weeks later. Median levels (red lines) were below the limit of detection for the +2h, and +6h arms and 14•9 fmols/10⁶ cells for the +24h arm and the +24h/+48h arm. Values below the LLOQ were assigned an arbitrary value of 10 fmol TFV-DP/10⁶ cells or half of the LLOQ.

Fig 6

Efficacy estimates for PrEP/PEP with oral FTC/TAF/EVG/COBI. Values reflect point estimates achieved with single doses as PrEP or PEP, or two doses as PEP. Horizontal lines denote the 95% confidence intervals. The closer the administration of the PrEP or PEP doses to the time of SHIV exposure the higher the efficacy.