Multiscale Systems-Pharmacology Pipeline to Assess the Prophylactic Efficacy of NRTIs Against HIV-1

Abstract

While HIV-1 continues to spread, the use of antivirals in preexposure prophylaxis (PrEP) has recently been suggested. Here we present a modular systems pharmacology modeling pipeline, predicting PrEP efficacy of nucleotide reverse transcriptase inhibitors (NRTIs) at the scale of reverse transcription, target-cell, and systemic infection and after repeated viral exposures, akin to clinical trials. We use this pipeline to benchmark the prophylactic efficacy of all currently approved NRTIs in wildtype and mutant viruses. By integrating pharmacokinetic models, we find that intracellular tenofovir-diphosphate builds up too slowly to halt infection when taken "on demand" and that lamivudine may substitute emtricitabine in PrEP combinations. Lastly, we delineate factors confounding clinical PrEP efficacy estimates and provide a method to overcome these. The presented framework is useful to screen and optimize PrEP candidates and strategies and to understand their clinical efficacy by integrating the diverse scales which determine PrEP efficacy.

Figure 1

Modular modeling framework. The virus replication model (module III) can be used to compute the probability of infection of an exposed person after viral challenge, given a particular drug inhibition (input from module II) and viral exposure (input from module IV). Model details are elaborated in Supplementary Note 3. Module IV represents a statistical model of the relation between the viral load in a transmitter, the mode of transmission (e.g., homosexual contact) and the number of viruses entering a target cell compartment in the exposed person. It is derived in Supplementary Note 4, where the parametrization is also given. The mechanisms of action model (MMOA) provides the link between intracellular NRTI‐TP concentrations, target process inhibition ε (reverse transcriptase‐mediated polymerization), and inhibition of target cell infection η. It can be used to quantify effects of all currently approved NRTIs and NRTI combinations, including inhibition of mutant viruses; see Supplementary Note 2 for details and model parameters. Pharmacokinetic models (module I), which establish the link between prodrug administration and intracellularly active NRTI‐TPs have been developed for TDF, FTC, and 3TC and allow to evaluate different PrEP strategies (e.g., dosing regimen), related to these compounds (summarized in Supplementary Note 1). Finally, module V can be used to assess the efficacy of PrEP strategies in preventing infection after multiple viral challenges ω_T, akin to clinical trials (see Supplementary Note 5 for derivations).

Figure 2

Virus exposure model (module IV). a: Virus load distribution ( ${\log }_{10}$ scale) in a representative transmitter population (German Sero‐converter study8, 27). b: Estimated distribution of virus exposure in a target cell environment n following unprotected hetero‐ and homosexual intercourse (blue and orange bars) with an infected individual. Inset: Probability that $\ge 1$ virus enters a replication‐relevant compartment. Derivations are provided in Supplementary Note 4.

Figure 3

Target‐cell NRTI‐TP concentration vs. risk reduction in wildtype and mutant viruses (modules II‐IV) ψ. a: Mean efficacies (% infections prevented) following viral exposure during a single unprotected homosexual intercourse (Eq. 3) are illustrated by the dotted lines. Solid thick lines mark the risk reduction profile at clinically relevant ranges for the respective drugs (indicated ranges only provide a rough guidance as outlined in Supplementary Note 3). Shaded areas indicate the corresponding IQR of the efficacy estimate, taking variability in microscopic parameters (module II) and virus exposure (module IV, Figure 2b) into account. b–d: Mean efficacies ψ of TDF, FTC, and 3TC against the wildtype virus are highlighted by solid lines. Efficacies against mutant viruses combine both drug effects and inherent fitness defects of the mutants. The relative reduction in infection with the mutant virus in the presence of drug vs. the wildtype virus in the absence of drugs is evaluated (dashed line: M184V, dash‐dotted line: K65R, dotted line M184V/K65R double mutant), see section “Concentration vs. risk reduction in wildtype and mutant viruses” for details. Vertical black dashed lines indicate the clinically relevant drug concentrations range after chronic therapy.

Figure 4

Efficacy ψ of PrEP “on demand” against infection following unprotected homosexual intercourse within 24hours after PrEP initiation (modules I‐IV). a–c: Pharmacokinetic profiles during PrEP “on demand” for the circulating NRTI prodrug (solid lines) and the intracellular, active NRTI‐TP moiety (dashed lines). FTC oral dose was 400 mg at 0 hours, followed by 200 mg at 24 and 48 hours (a), while TDF or 3TC dosage was 600 mg at 0 hours, followed by 300 mg at 24 and 48 hours, respectively. d–e: Infections averted for PrEP “on demand” when viral challenge occurred either 1, 3, 6, 12, 18, or 24 hours after PrEP initiation with either FTC (d), TDF (e), or 3TC (f). Solid lines indicate the mean % infections averted (see Eq. 3), while shaded areas indicate interquartile ranges of this estimate, taking variability in microscopic parameters (module II) and virus exposure during homosexual intercourse (module IV, Figure 2b) into account. g,h: Infections averted for combinations of TDF+FTC (g) and TDF+3TC (h), taken “on demand” (double doses at day 0, followed by single doses at days 1, 2). Combination predictions assumed that no significant pharmacokinetic interactions occur, pharmacodynamic interactions were modeled as outlined in Supplementary Note 2.

Figure 5

Risk reduction profile ψ for an unprotected homosexual intercourse occurring within 30 days of PrEP or after its discontinuation (modules I‐IV). a–e: Mean risk reduction profiles (see Eq. 3) when either oral doses of 200 mg FTC (a), 300 mg TDF (b), 300 mg 3TC (c), 300 mg TDF+200 mg FTC (d), 300 mg TDF+300 mg 3TC (e) were administered daily for 30 days and discontinued thereafter are illustrated by solid lines. Shaded areas indicate interquartile ranges of this estimate, taking variability in microscopic parameters (module II) and virus exposure during homosexual intercourse (module IV, Figure 2b) into account. f: The mean risk reduction profile for the combination 300 mg TDF + 200 mg FTC (violet solid line) is shown together with the mean risk reduction profiles for the single drugs FTC (green) and TDF (red). g: The mean risk reduction profile for the combination 300 mg TDF + 300 mg 3TC (orange solid line) is shown together with the mean risk reduction profiles for the single drugs 3TC (blue) and TDF (red). Combination predictions assumed that no significant pharmacokinetic interactions occur, pharmacodynamic interactions were modeled as outlined in Supplementary Note 2.