Antiviral efficacy of favipiravir against Ebola virus: A translational study in cynomolgus macaques

English version České info

Background:
Despite repeated outbreaks, in particular the devastating 2014–2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD). Among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with EVD (JIKI trial) but did not demonstrate a strong antiviral efficacy. In order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management of future outbreaks, we assess the efficacy achieved by ascending doses of favipiravir in Ebola-virus-infected nonhuman primates (NHPs).

Methods and findings:
A total of 26 animals (Macaca fascicularis) were challenged intramuscularly at day 0 with 1,000 focus-forming units of Ebola virus Gabon 2001 strain and followed for 21 days (study termination). This included 13 animals left untreated and 13 treated with doses of 100, 150, and 180 mg/kg (N = 3, 5, and 5, respectively) favipiravir administered intravenously twice a day for 14 days, starting 2 days before infection. All animals left untreated or treated with 100 mg/kg died within 10 days post-infection, while animals receiving 150 and 180 mg/kg had extended survival (P < 0.001 and 0.001, respectively, compared to untreated animals), leading to a survival rate of 40% (2/5) and 60% (3/5), respectively, at day 21. Favipiravir inhibited viral replication (molecular and infectious viral loads) in a drug-concentration-dependent manner (P values < 0.001), and genomic deep sequencing analyses showed an increase in virus mutagenesis over time. These results allowed us to identify that plasma trough favipiravir concentrations greater than 70–80 μg/ml were associated with reduced viral loads, lower virus infectivity, and extended survival. These levels are higher than those found in the JIKI trial, where patients had median trough drug concentrations equal to 46 and 26 μg/ml at day 2 and day 4 post-treatment, respectively, and suggest that the dosing regimen in the JIKI trial was suboptimal. The environment of a biosafety level 4 laboratory introduces a number of limitations, in particular the difficulty of conducting blind studies and performing detailed pharmacological assessments. Further, the extrapolation of the results to patients with EVD is limited by the fact that the model is fully lethal and that treatment initiation in patients with EVD is most often initiated several days after infection, when symptoms and high levels of viral replication are already present.

Conclusions:
Our results suggest that favipiravir may be an effective antiviral drug against Ebola virus that relies on RNA chain termination and possibly error catastrophe. These results, together with previous data collected on tolerance and pharmacokinetics in both NHPs and humans, support a potential role for high doses of favipiravir for future human interventions.

Vyšlo v časopise: Antiviral efficacy of favipiravir against Ebola virus: A translational study in cynomolgus macaques. PLoS Med 15(3): e32767. doi:10.1371/journal.pmed.1002535
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1002535

Souhrn

Zdroje

1. World Health Organization. Situation report: Ebola virus disease. Geneva: World Health Organization; 2016 Jun 10 [cited 2018 Feb 22]. Available from: http://apps.who.int/iris/bitstream/10665/208883/1/ebolasitrep_10Jun2016_eng.pdf?ua=1.

2. Sissoko D, Laouenan C, Folkesson E, M’lebing A-B, Beavogui A-H, Baize S, et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in Guinea. PLoS Med. 2016;13:e1001967. doi: 10.1371/journal.pmed.1001967 26930627

3. Dunning J, Kennedy SB, Antierens A, Whitehead J, Ciglenecki I, Carson G, et al. Experimental treatment of Ebola virus disease with brincidofovir. PLoS ONE. 2016;11:e0162199. doi: 10.1371/journal.pone.0162199 27611077

4. PREVAIL II Writing Group, Multi-National PREVAIL II Study Team. A Randomized, controlled trial of ZMapp for Ebola virus infection. N Engl J Med. 2016;375:1448–56. doi: 10.1056/NEJMoa1604330 27732819

5. Dunning J, Sahr F, Rojek A, Gannon F, Carson G, Idriss B, et al. Experimental treatment of Ebola virus disease with TKM-130803: a single-arm phase 2 clinical trial. PLoS Med. 2016;13:e1001997. doi: 10.1371/journal.pmed.1001997 27093560

6. Van Griensven J, Edwards T, De Lamballerie X, Semple MG, Gallian P, Baize S, et al. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med. 2016;374:33–42. doi: 10.1056/NEJMoa1511812 26735992

7. World Health Organization. Categorization and prioritization of drugs for consideration for testing or use in patients infected with Ebola. Geneva: World Health Organization; 2015 Jul 3 [cited 2015 Sep 7]. Available from: http://www.who.int/medicines/ebola-treatment/2015_0703TablesofEbolaDrugs.pdf?ua=1.

8. Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res. 2014;105:17–21. doi: 10.1016/j.antiviral.2014.02.014 24583123

9. Smither SJ, Eastaugh LS, Steward JA, Nelson M, Lenk RP, Lever MS. Post-exposure efficacy of oral T-705 (favipiravir) against inhalational Ebola virus infection in a mouse model. Antiviral Res. 2014;104:153–5. doi: 10.1016/j.antiviral.2014.01.012 24462697

10. Madelain V, Nguyen THT, Olivo A, De Lamballerie X, Guedj J, Taburet A-M, et al. Ebola virus infection: review of the pharmacokinetic and pharmacodynamic properties of drugs considered for testing in human efficacy trials. Clin Pharmacokinet. 2016;55:907–23. doi: 10.1007/s40262-015-0364-1 26798032

11. Piorkowski G, Jacquot F, Quérat G, Carbonnelle C, Pannetier D, Mentré F, et al. Implementation of a non-human primate model of Ebola disease: infection of Mauritian cynomolgus macaques and analysis of virus populations. Antiviral Res. 2017;140:95–105. doi: 10.1016/j.antiviral.2017.01.017 28132865

12. Nguyen THT, Guedj J, Anglaret X, Laouénan C, Madelain V, Taburet A-M, et al. Favipiravir pharmacokinetics in Ebola-infected patients of the JIKI trial reveals concentrations lower than targeted. PLoS Negl Trop Dis. 2017;11:e0005389. doi: 10.1371/journal.pntd.0005389 28231247

13. Madelain V, Guedj J, Mentré F, Nguyen THT, Jacquot F, Oestereich L, et al. Favipiravir pharmacokinetics in nonhuman primates and insights for future efficacy studies of hemorrhagic fever viruses. Antimicrob Agents Chemother. 2017;61:e01305–16. doi: 10.1128/AAC.01305-16 27736754

14. Mentré F, Taburet A-M, Guedj J, Anglaret X, Keïta S, de Lamballerie X, et al. Dose regimen of favipiravir for Ebola virus disease. Lancet Infect Dis. 2015;15:150–1. doi: 10.1016/S1473-3099(14)71047-3 25435054

15. Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;514:47–53. doi: 10.1038/nature13777 25171469

16. Gibb TR, Norwood DA, Woollen N, Henchal EA. Development and evaluation of a fluorogenic 5′ nuclease assay to detect and differentiate between Ebola virus subtypes Zaire and Sudan. J Clin Microbiol. 2001;39:4125–30. doi: 10.1128/JCM.39.11.4125-4130.2001 11682540

17. Gowen BB, Sefing EJ, Westover JB, Smee DF, Hagloch J, Furuta Y, et al. Alterations in favipiravir (T-705) pharmacokinetics and biodistribution in a hamster model of viral hemorrhagic fever. Antiviral Res. 2015;121:132–7. doi: 10.1016/j.antiviral.2015.07.003 26186980

18. Baranovich T, Wong S-S, Armstrong J, Marjuki H, Webby RJ, Webster RG, et al. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J Virol. 2013;87:3741–51. doi: 10.1128/JVI.02346-12 23325689

19. de Ávila AI, Gallego I, Soria ME, Gregori J, Quer J, Esteban JI, et al. Lethal mutagenesis of hepatitis C virus induced by favipiravir. PLoS ONE. 2016;11:e0164691. doi: 10.1371/journal.pone.0164691 27755573

20. de Avila AI, Moreno E, Perales C, Domingo E. Favipiravir can evoke lethal mutagenesis and extinction of foot-and-mouth disease virus. Virus Res. 2017;233:105–12. doi: 10.1016/j.virusres.2017.03.014 28322918

21. Escribano-Romero E, de Oya NJ, Domingo E, Saiz JC. Extinction of West Nile virus by favipiravir through lethal mutagenesis. Antimicrob Agents Chemother. 2017;61:e01400–17.

22. Sangawa H, Komeno T, Nishikawa H, Yoshida A, Takahashi K, Nomura N, et al. Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. Antimicrob Agents Chemother. 2013;57:5202–8. doi: 10.1128/AAC.00649-13 23917318

23. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. 2000;355:827–35. doi: 10.1016/S0140-6736(99)11433-8 10711940

24. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531:381–5. doi: 10.1038/nature17180 26934220

25. Geisbert TW, Hensley LE, Larsen T, Young HA, Reed DS, Geisbert JB, et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am J Pathol. 2003;163:2347–70. doi: 10.1016/S0002-9440(10)63591-2 14633608

26. Geisbert TW, Strong JE, Feldmann H. Considerations in the use of nonhuman primate models of Ebola virus and Marburg virus infection. J Infect Dis. 2015;212:S91–7. doi: 10.1093/infdis/jiv284 26063223

27. Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, et al. Mechanism of action of T-705 against influenza virus. Antimicrob Agents Chemother. 2005;49:981–6. doi: 10.1128/AAC.49.3.981-986.2005 15728892

28. Smee DF, Hurst BL, Egawa H, Takahashi K, Kadota T, Furuta Y. Intracellular metabolism of favipiravir (T-705) in uninfected and influenza A (H5N1) virus-infected cells. J Antimicrob Chemother. 2009;64:741–6. doi: 10.1093/jac/dkp274 19643775

29. Bai C-Q, Mu J-S, Kargbo D, Song Y-B, Niu W-K, Nie W-M, et al. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705), Sierra Leone, 2014. Clin Infect Dis. 2016;63:1288–94. doi: 10.1093/cid/ciw571 27553371

30. Faye O, Andronico A, Faye O, Salje H, Boëlle P-Y, Magassouba N, et al. Use of viremia to evaluate the baseline case fatality ratio of Ebola virus disease and inform treatment studies: a retrospective cohort study. PLoS Med. 2015;12:e1001908. doi: 10.1371/journal.pmed.1001908 26625118

31. Thi EP, Mire CE, Lee AC, Geisbert JB, Zhou JZ, Agans KN, et al. Lipid nanoparticle siRNA treatment of Ebola-virus-Makona-infected nonhuman primates. Nature. 2015;521:362–5. doi: 10.1038/nature14442 25901685

32. Sissoko D, Duraffour S, Kerber R, Kolie JS, Beavogui AH, Camara A-M, et al. Persistence and clearance of Ebola virus RNA from seminal fluid of Ebola virus disease survivors: a longitudinal analysis and modelling study. Lancet Glob Health. 2017;5:e80–8. doi: 10.1016/S2214-109X(16)30243-1 27955791

33. Subtil F, Delaunay C, Keita A, Sow M, Touré A, Leroy S, et al. Dynamics of Ebola RNA persistence in semen: report from the Postebogui cohort in Guinea. Clin Infect Dis. 2017;64:1788–90. doi: 10.1093/cid/cix210 28329169

34. Jacobs M, Rodger A, Bell DJ, Bhagani S, Cropley I, Filipe A, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet. 2016;388:498–503. doi: 10.1016/S0140-6736(16)30386-5 27209148

35. Henao-Restrepo AM, Longini IM, Egger M, Dean NE, Edmunds WJ, Camacho A, et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet. 2015;386:857–66. doi: 10.1016/S0140-6736(15)61117-5 26248676

36. Kennedy SB, Bolay F, Kieh M, Grandits G, Badio M, Ballou R, et al. Phase 2 placebo-controlled trial of two vaccines to prevent Ebola in liberia. N Engl J Med. 2017;377:1438–47. doi: 10.1056/NEJMoa1614067 29020589

37. Winslow RL, Milligan ID, Voysey M, Luhn K, Shukarev G, Douoguih M, et al. Immune responses to novel adenovirus type 26 and modified vaccinia virus Ankara-vectored Ebola vaccines at 1 year. JAMA. 2017;317:1075–7. doi: 10.1001/jama.2016.20644 28291882

38. Oestereich L, Rieger T, Neumann M, Bernreuther C, Lehmann M, Krasemann S, et al. Evaluation of antiviral efficacy of ribavirin, arbidol, and T-705 (favipiravir) in a mouse model for Crimean-Congo hemorrhagic fever. PLoS Negl Trop Dis. 2014;8:e2804. doi: 10.1371/journal.pntd.0002804 24786461

39. Oestereich L, Rieger T, Lüdtke A, Ruibal P, Wurr S, Pallasch E, et al. Efficacy of favipiravir alone and in combination with ribavirin in a lethal, immunocompetent mouse model for Lassa fever. J Infect Dis. 2016;213:934–8. doi: 10.1093/infdis/jiv522 26531247

40. Best K, Guedj J, Madelain V, Lamballerie X de, Lim S-Y, Osuna CE, et al. Zika plasma viral dynamics in nonhuman primates provides insights into early infection and antiviral strategies. Proc Natl Acad Sci U S A. 2017;114:8847–52. doi: 10.1073/pnas.1704011114 28765371