Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir

Abstract

Background: In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission.

Methods and findings: We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected.

Conclusions: This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.

Figure 1. Study Design and Interventions

(A) Daily PrEP. Macaques were drug-treated 7–9 d before the first virus inoculation. Treated animals that remained negative during the 14 challenges received drug for an additional 28 d. Treated animals that became infected continued treatment to monitor plasma viremia and drug resistance emergence. (B) Intermittent PrEP. Macaques received FTC and tenofovir only 2 h before and 24 h after each weekly rectal challenge. (C) Untreated control macaques. Infection of macaques was monitored weekly by PCR and serologic testing. The treatment groups were staggered; four of 33 macaques were used in two separate arms (see Methods, Text S1, and Table S1).

Figure 2. Protection against Repeated Rectal Virus Exposures by Daily or Intermittent PrEP

Each survival curve represents the cumulative proportion of uninfected macaques as a function of the number of weekly rectal exposures. Protected animals in groups 1–4 remained negative after a mean washout out of 27 wk (range, 17–60 wk).

Figure 3. Breakthrough Infections during PrEP Show Blunted Acute Viremias

Each time point represents the mean virus load observed in treated (n = 6) or untreated control (n = 10) macaques. Time 0 indicates the peak plasma virus load. Bars denote the standard error of the mean.

Figure 4. Dynamics of Infection in Animals Infected during PrEP with FTC (AG-80, AG-46, AH-04, and AG-07) or FTC/TDF (AG-81 and AI-54)

Red circles indicate detectable M184V/I mutation; wild-type sequences are shown in blue. Open circles indicate time points that were not genotyped. The first detectable antibody response is shown as red arrows. The broken line denotes the limit of detection of the virus load assay (50 copies/ml).