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

Overview

Journal CPT Pharmacometrics Syst Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2016 Jul 22

PMID 27439573

Citations 13

Authors

S Duwal

V Sunkara

M von Kleist

Affiliations

Soon will be listed here.

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.

Citing Articles

Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subcutaneous implant.

Kim H, Zhang L, Hendrix C, Haberer J, von Kleist M CPT Pharmacometrics Syst Pharmacol. 2024; 13(10):1693-1706.

PMID: 39164932 PMC: 11494919. DOI: 10.1002/psp4.13212.

Ex-vivo rectal tissue infection with HIV-1 to assess time to protection following oral preexposure prophylaxis with tenofovir disoproxil/emtricitabine.

Chawki S, Goldwirt L, Mouhebb M, Gabassi A, Taouk M, Bichard I AIDS. 2023; 38(4):455-464.

PMID: 37976073 PMC: 10906210. DOI: 10.1097/QAD.0000000000003789.

Pharmacokinetic Model of Tenofovir and Emtricitabine and Their Intracellular Metabolites in Patients in the ANRS 134-COPHAR 3 Trial Using Dose Records.

Bertrand J, Barrail-Tran A, Fayette L, Savic R, Goujard C, Teicher E Antimicrob Agents Chemother. 2023; 67(5):e0233918.

PMID: 37098914 PMC: 10190280. DOI: 10.1128/aac.02339-18.

HIV pre-exposure prophylaxis adherence test using reverse transcription isothermal amplification inhibition assay.

Zhang J, Zhang Y, Bender A, Sullivan B, Olanrewaju A, Lillis L Anal Methods. 2022; 14(13):1361-1370.

PMID: 35297917 PMC: 8991996. DOI: 10.1039/d2ay00008c.

Numerical approaches for the rapid analysis of prophylactic efficacy against HIV with arbitrary drug-dosing schemes.

Zhang L, Wang J, von Kleist M PLoS Comput Biol. 2021; 17(12):e1009295.

PMID: 34941864 PMC: 8741042. DOI: 10.1371/journal.pcbi.1009295.

References

von Kleist M, Huisinga W . Pharmacokinetic-pharmacodynamic relationship of NRTIs and its connection to viral escape: an example based on zidovudine. Eur J Pharm Sci. 2009; 36(4-5):532-43. DOI: 10.1016/j.ejps.2008.12.010. View

Anderson P, Kakuda T, Lichtenstein K . The cellular pharmacology of nucleoside- and nucleotide-analogue reverse-transcriptase inhibitors and its relationship to clinical toxicities. Clin Infect Dis. 2004; 38(5):743-53. DOI: 10.1086/381678. View

Bartmeyer B, Kuecherer C, Houareau C, Werning J, Keeren K, Somogyi S . Prevalence of transmitted drug resistance and impact of transmitted resistance on treatment success in the German HIV-1 Seroconverter Cohort. PLoS One. 2010; 5(10):e12718. PMC: 2951346. DOI: 10.1371/journal.pone.0012718. View

Painter G, Almond M, Mao S, Liotta D . Biochemical and mechanistic basis for the activity of nucleoside analogue inhibitors of HIV reverse transcriptase. Curr Top Med Chem. 2004; 4(10):1035-44. DOI: 10.2174/1568026043388358. View

Plosker G . Emtricitabine/tenofovir disoproxil fumarate: a review of its use in HIV-1 pre-exposure prophylaxis. Drugs. 2013; 73(3):279-91. DOI: 10.1007/s40265-013-0024-4. View

Duwal S, von Kleist M . Top-down and bottom-up modeling in system pharmacology to understand clinical efficacy: An example with NRTIs of HIV-1. Eur J Pharm Sci. 2016; 94:72-83. DOI: 10.1016/j.ejps.2016.01.016. View

Sagaon-Teyssier L, Suzan-Monti M, Demoulin B, Capitant C, Lorente N, Preau M . Uptake of PrEP and condom and sexual risk behavior among MSM during the ANRS IPERGAY trial. AIDS Care. 2016; 28 Suppl 1:48-55. PMC: 4828609. DOI: 10.1080/09540121.2016.1146653. View

Menendez-Arias L . Molecular basis of human immunodeficiency virus drug resistance: an update. Antiviral Res. 2009; 85(1):210-31. DOI: 10.1016/j.antiviral.2009.07.006. View

Weber J, Chakraborty B, Weberova J, Miller M, Quinones-Mateu M . Diminished replicative fitness of primary human immunodeficiency virus type 1 isolates harboring the K65R mutation. J Clin Microbiol. 2005; 43(3):1395-400. PMC: 1081293. DOI: 10.1128/JCM.43.3.1395-1400.2005. View

10.

Madrasi K, Burns R, Hendrix C, Fossler M, Chaturvedula A . Linking the population pharmacokinetics of tenofovir and its metabolites with its cellular uptake and metabolism. CPT Pharmacometrics Syst Pharmacol. 2014; 3:e147. PMC: 4260001. DOI: 10.1038/psp.2014.46. View

11.

Velter A, Barin F, Bouyssou A, Guinard J, Leon L, Le Vu S . HIV prevalence and sexual risk behaviors associated with awareness of HIV status among men who have sex with men in Paris, France. AIDS Behav. 2012; 17(4):1266-78. DOI: 10.1007/s10461-012-0303-1. View

12.

Chun T, Moir S, Fauci A . HIV reservoirs as obstacles and opportunities for an HIV cure. Nat Immunol. 2015; 16(6):584-9. DOI: 10.1038/ni.3152. View

13.

Attia S, Egger M, Muller M, Zwahlen M, Low N . Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis. AIDS. 2009; 23(11):1397-404. DOI: 10.1097/QAD.0b013e32832b7dca. View

14.

Duwe S, Brunn M, Altmann D, Hamouda O, Schmidt B, Walter H . Frequency of genotypic and phenotypic drug-resistant HIV-1 among therapy-naive patients of the German Seroconverter Study. J Acquir Immune Defic Syndr. 2001; 26(3):266-73. DOI: 10.1097/00042560-200103010-00010. View

15.

Cottrell M, Yang K, Prince H, Sykes C, White N, Malone S . A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine. J Infect Dis. 2016; 214(1):55-64. PMC: 4907409. DOI: 10.1093/infdis/jiw077. View

16.

Lewis W, Day B, Copeland W . Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Discov. 2003; 2(10):812-22. DOI: 10.1038/nrd1201. View

17.

Garcia-Lerma J, Aung W, Cong M, Zheng Q, Youngpairoj A, Mitchell J . Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. J Virol. 2011; 85(13):6610-7. PMC: 3126530. DOI: 10.1128/JVI.00311-11. View

18.

Grant R, Lama J, Anderson P, McMahan V, Liu A, Vargas L . Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010; 363(27):2587-99. PMC: 3079639. DOI: 10.1056/NEJMoa1011205. View

19.

Bazzoli C, Jullien V, Le Tiec C, Rey E, Mentre F, Taburet A . Intracellular Pharmacokinetics of Antiretroviral Drugs in HIV-Infected Patients, and their Correlation with Drug Action. Clin Pharmacokinet. 2009; 49(1):17-45. DOI: 10.2165/11318110-000000000-00000. View

20.

Abraham B, Gulick R . Next-generation oral preexposure prophylaxis: beyond tenofovir. Curr Opin HIV AIDS. 2012; 7(6):600-6. PMC: 3732461. DOI: 10.1097/COH.0b013e328358b9ce. View