Mechanistic framework predicts drug-class specific utility of antiretrovirals for HIV prophylaxis

Abstract

Currently, there is no effective vaccine to halt HIV transmission. However, pre-exposure prophylaxis (PrEP) with the drug combination Truvada can substantially decrease HIV transmission in individuals at risk. Despite its benefits, Truvada-based PrEP is expensive and needs to be taken once-daily, which often leads to inadequate adherence and incomplete protection. These deficits may be overcome by next-generation PrEP regimen, including currently investigated long-acting formulations, or patent-expired drugs. However, poor translatability of animal- and ex vivo/in vitro experiments, and the necessity to conduct long-term (several years) human trials involving considerable sample sizes (N>1000 individuals) are major obstacles to rationalize drug-candidate selection. We developed a prophylaxis modelling tool that mechanistically considers the mode-of-action of all available drugs. We used the tool to screen antivirals for their prophylactic utility and identify lower bound effective concentrations that can guide dose selection in PrEP trials. While in vitro measurable drug potency usually guides PrEP trial design, we found that it may over-predict PrEP potency for all drug classes except reverse transcriptase inhibitors. While most drugs displayed graded concentration-prophylaxis profiles, protease inhibitors tended to switch between none- and complete protection. While several treatment-approved drugs could be ruled out as PrEP candidates based on lack-of-prophylactic efficacy, darunavir, efavirenz, nevirapine, etravirine and rilpivirine could more potently prevent infection than existing PrEP regimen (Truvada). Notably, some drugs from this candidate set are patent-expired and currently neglected for PrEP repurposing. A next step is to further trim this candidate set by ruling out compounds with ominous safety profiles, to assess different administration schemes in silico and to test the remaining candidates in human trials.

Fig 1. Schematic of the HIV replication cycle and mechanism of interference by treatment-approved drug classes.

Free viruses are cleared by the immune system with a rate constant CL. Further, free viruses can be also cleared during unsuccessful T-cell infection CL_T through the destruction of essential viral components of the reverse transcription-, or pre-integration complex [37, 38]. The term β represents the lumped rate of infection of T-cells, including the processes of virus attachment to the cell, fusion and reverse transcription, leading to an early infected cell T₁, before proviral integration. Similarly, the term k denotes the rate by which early infected T₁ cells are transformed into productively infected T₂ cells, involving proviral integration and cellular reprogramming. The term N_T denotes the rate of production of infectious virus progeny by productively infected T₂ cells. The rates β, CL_T, k and N_T may be modified by different antiretrovirals as indicated by bars (inhibition) and pointers with plus sign (drug-dependent increase). The terms ${\delta }_{T_1}<{\delta }_{T_2}$ denote the rates of clearance of T₁ and T₂ cells respectively and δ_PIC denotes the rate of intracellular destruction of the pre-integration complex. CRA: Co-receptor antagonists, RTIs: reverse transcriptase inhibitors, InIs: Integrase inhibitors, PIs: Protease inhibitors.

Fig 2. Relation between direct drug effect and prophylactic efficacy.

The relation between direct drug effect η and prophylactic efficacy φ (reduction in infection) is shown for different drug classes utilizing the viral model depicted in Fig 1 with parameters stated in Table 1. Panel A: Relation between η and φ when a single virus $Y_0=\hat{V}$ reached a replication-enabling compartment in the virus-exposed individual. Panel B: Relation between η and φ when a single early infected cell $Y_0={\hat{T}}_1$ or (panel C) a late infected T-cell $Y_0={\hat{T}}_2$ reached a replication-enabling compartment. Solid red lines: CRAs, solid green line: RTIs, dashed blue line: InI, dashed purple line: PIs.

Fig 3. Shape of the concentration-prophylaxis profile.

Colored lines depict the concentration-prophylaxis profile for an average drug class-specific slope parameter $\bar{m}$ in Eq (10). Solid colored line for an inoculum of one virus $Y_0=\hat{V}$ and dashed colored line for an inoculum of $Y_0=100\cdot \hat{V}$. Shaded areas indicate the concentration-prophylaxis profile for the smallest m_min and largest class-specific slope parameter m_max for the respective drug class as indicated in Table 2. A: Co-receptor antagonists. Currently only one co-receptor antagonist, maraviroc, is approved. We use $\bar{m}=m_{min}=0.61$ and also plot m_max = 1 as a reference. B: Non-nucleoside reverse transcriptase inhibitors (NNRTIs); $\bar{m}=1.71$, m_min = 1.55 and m_max = 1.92. Nucleoside reverse transcriptase inhibitors (NRTI) have been analyzed in [18]. C: Integrase inhibitors, $\bar{m}=1.12$, m_min = 0.95 and m_max = 1.3. D: Protease inhibitors; $\bar{m}=2.87$, m_min = 1.81 and m_max = 4.53. Utilized virus dynamics parameters are stated in Table 1.

Fig 4. Drug specific prophylactic efficacy.

Solid and dashed colored lines depict the concentration-prophylaxis profile for the individual drugs. The solid lines represent the concentration-prophylaxis profiles and light and dark grey areas indicate the quartile ranges and 5-95% ranges of the concentration-prophylaxis profile, considering uncertainty in pharmacodynamic parameters (Table 2) and the distribution of viral inoculum sizes after homosexual exposure to HIV using the virus exposure model’ (Methods section and [18]). Maximum clinically achievable concentrations C_max for chronic oral administration of the standard dosing regimen and a lower bound concentration C_low that would be achieved if the last dose had been taken three days prior to virus exposure are marked by thick and thin vertical black dashed lines respectively. For IDV, LPV, NFV and SQV C_low falls below the range of the x-axis. Downward pointing arrows indicate minimum (pre-dose) concentrations achieved for standard regimen in adherent individuals as reported in [40], [96] and [95]. MVC -maraviroc, EFV -efavirenz, NVP -nevirapine, DLV -delavirdine, ETR -etravirine, RPV -rilpivirine, RAL -raltegravir, EVG -elvitegravir, DTG -dolutegravir, ATV -atazanavir, APV -amprenavir, DRV -darunavir, IDV -indinavir, LPV -lopinavir, NFV -nelfinavir, SQV -saquinavir, TPV -tipranavir. *recently or currently tested for PrEP.