Modelling the impact of initiation delay, duration and prior PrEP on the efficacy of post-exposure prophylaxis containing a tenofovir/emtricitabine backbone

Abstract

Introduction: Pre- and post-exposure prophylaxis (PrEP and PEP) are important pillars of the HIV prevention portfolio to reduce the risk of acquisition just before or after HIV exposure. While PrEP efficacy has been elucidated in many randomized clinical trials, corresponding data for PEP is extremely difficult to obtain in a controlled setting. Consequently, it is almost impossible to study the impact of PEP initiation delay and duration on HIV risk reduction clinically, which would inform recommendations on PEP use.

Methods: We employ pharmacokinetics, pharmacodynamics and viral dynamics models, along with individual factors, such as drug adherence to investigate the impact of initiation delay and PEP duration on HIV risk reduction. We evaluated PEP using two- and three-drug regimens with a TDF/FTC backbone. Moreover, we study PEP efficacy in the context of PrEP-to-PEP transitions.

Results: In our simulations, early initiation of PEP emerged as a pivotal factor for HIV risk reduction. We found that 2-drug (TDF/FTC) PEP may insufficiently protect when initiated > 1 hour post-exposure. When adding a third drug, early initiation was still a critical factor; however, over 90% efficacy could be achieved when PEP was initiated 48 hours post-exposure and taken for at least 14-28 days, depending on the efficacy of the third-drug component. When investigating PrEP-PEP transitions, we observed that preceding PrEP can (1) contribute directly to prophylactic efficacy, and (2) boost subsequent PEP efficacy by delaying initial viral dynamics and building-up drug concentrations, overall facilitating self-managed transitioning between PrEP and PEP.

Conclusions: Our study confirms the critical role of early (< 48 hours) PEP initiation, preferably with three drugs taken for 28 days. Self-start with TDF/FTC and later addition of a third drug is better than not self-starting. Furthermore, our study highlights the synergy between recent PrEP intake and PEP and may help to inform recommendations on PEP use.

Keywords: HIV; TDF/FTC; mathematical modelling; post‐exposure prophylaxis; pre‐exposure prophylaxis; quantitative systems pharmacology.

Figure 1

Schematic of post‐exposure prophylaxis and key parameters influencing PEP efficacy in the mathematical model. (a) PEP is initiated after virus exposure. In the time between virus exposure and PEP initiation, virus may grow exponentially. The total amount of virus replication during this time may be related to the probability of emergence of latently infected cells, which render infection irreversible (grey area). Depending on the duration of viral growth before PEP and conditioned that latent infected cells have not yet emerged, PEP must be taken long enough to ensure that all replicating viruses are eliminated. (b) Schematic of model constituents for estimating PEP efficacy. Pharmacokinetic models relate arbitrary dosing patterns to target site concentration‐time profiles. Through mechanism‐of‐action models, we predict their impact of early viral dynamics. Lastly, we compute the probability that all virus compartments will be eliminated during PEP, after a particular viral exposure occurred. We use these integrated models to calculate the per exposure reduction in HIV acquisition probability (PEP efficacy). Abbreviations: DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; PEP, post‐exposure prophylaxis; TDF, tenofovir disoproxil fumarate.

Figure 2

Sensitivity of TDF/FTC‐based PEP on initiation delay and PEP duration. (a) Schematic of the dosing regimen in panel C, where the variable tested is “time to PEP.” (b) Schematic of the dosing regimen in panel D, where the variable tested is “PEP duration.” (c) PEP efficacy of TDF/FTC (red line), TDF/FTC + EFV (blue line) or TDF/FTC + DTG (green line) when initiated at different delays post virus exposure and taken for 28 days once‐daily. The vertical dotted line indicates PEP initiation 1 hour after exposure. (d) Efficacy of TDF/FTC (red line), TDF/FTC + EFV (blue line) and TDF/FTC + DTG (green line) when initiated 48 hours post virus exposure and taken for different durations. (e) Numerical results for different “times to PEP,” “PEP durations” and regimen. Values denote the median efficacy and 95% confidence interval evaluated at the maximum “time to PEP” of the indicated interval (e.g. 8 hours for the 2–8 hours interval). All computations were conducted on 1000 virtual patients. The daily oral dose for each drug corresponds to 300/200 mg TDF/FTC, 50 mg DTG and 400 mg EFV. The coloured lines depict the median predicted PEP efficacy, whereas the dark‐ and light grey areas present the inter‐quartile range and the 95% confidence range, respectively. Dashed horizontal lines indicate 90% prophylactic efficacy. Abbreviations: DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; PEP, post‐exposure prophylaxis; TDF, tenofovir disoproxil fumarate.

Figure 3

Efficacy of TDF/FTC‐based PEP with delayed initiation of TDF/FTC and further delay of the third drug. (a) Schematic of the dosing regimen. For the drug combinations TDF/FTC + DTG and TDF/FTC + EFV, PEP efficacy was computed for virus exposures occurring within 1–48 hours before the first dose of TDF/FTC. The third drug was then added to the PEP regimen 1–7 days after the first dose of TDF/FTC. (b) PEP efficacy for the drug combination TDF/FTC + DTG, PEP duration was 14 days from the first dose of TDF/FTC. (c) Corresponding PEP efficacy for TDF/FTC + EFV. (d) PEP efficacy for TDF/FTC + DTG when taken for 28 days after the first TDF/FTC dose. (e) Corresponding PEP efficacy for TDF/FTC + EFV. The daily oral dose for each drug corresponds to 300/200 mg TDF/FTC, 50 mg DTG and 400 mg EFV. In panels B–E, the top row outlined in black denotes the scenario where the third drug is immediately added to the TDF/FTC backbone; the bottom row represents the scenario where no third drug was added to the TDF/FTC backbone. DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; PEP, post‐exposure prophylaxis; TDF, tenofovir disoproxil fumarate.

Figure 4

PEP efficacy following on‐demand PrEP. (a) Schematic of the dosing regimen. TDF/FTC was initially administered as “on‐demand” PrEP (2‐1‐1), followed by viral exposure after a certain period. Subsequently, the PEP regimen was initiated after various time intervals, potentially incorporating a third drug. (b–d) The efficacy profiles for PEP with overall duration of 14 days, and the exposure occurred 2, 5 and 7 days after the on‐demand PrEP, respectively. (f–h): The efficacy profiles for PEP with overall duration of 28 days. (e and i): PEP efficacy of baseline scenario without preceding PrEP. All computations were performed on 1000 virtual patients. The daily dose for each drug corresponds to 200 mg FTC, 300 mg TDF, 50 mg DTG and 400 mg EFV. The coloured lines represent the median efficacy value in cases where PEP was initiated at the respective time point along the x‐axis. Dashed horizontal lines indicate 90% prophylactic efficacy. The shaded areas depict the quantile range of prophylactic efficacy. Abbreviations: DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; PEP, post‐exposure prophylaxis; PrEP, pre‐exposure prophylaxis; TDF, tenofovir disoproxil fumarate.

Figure 5

Predicted efficacy of once‐daily PEP, in cases where PrEP was recently taken. (a) Schematic of dosing regimen: PrEP with incomplete, variable levels of adherence was taken and stopped 48 hours before virus exposure. PEP with either TDF/FTC, or TDF/FTC + DTG or EFV was then initiated after a variable delay and taken for 28 days. PEP efficacy is calculated with regard to preceding PrEP adherence, as well as delay in PEP initiation. (b–d) Computed prophylactic efficacy for the distinct PrEP+PEP regimen, if PEP was initiated 2, 3 or 5 days post‐exposure and taken daily for 28 days. The daily oral dose for each drug corresponds to 300/200 mg TDF/FTC, 50 mg DTG and 400 mg EFV. The grey‐shaded area indicates PEP efficacy, with no prior PrEP, while empty boxplots highlight the prophylactic effect of preceding PrEP, without subsequent PEP. Boxplots show the median, interquartile ranges and whiskers encompass the 95% confidence interval. Dashed red lines indicate 50% prophylactic efficacy, while dashed black lines indicate 90% prophylactic efficacy. Abbreviations: DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; PEP, post‐exposure prophylaxis; PrEP, pre‐exposure prophylaxis; TDF, tenofovir disoproxil fumarate.