Continued from my last blog post.
5. Corticosteroids (e.g. dexamethasone, hydrocortisone, methylprednisolone, prednisolone)
Corticosteroids are steroidal hormones that have anti-inflammatory functions, and are normally used to suppress inflammatory conditions resulting from immune system overdrive in fighting off infection. They were widely used in Hong Kong in the 2003 SARS epidemic.1
The results of using corticosteroids on coronavirus infected patients were contradictory and mostly unfavourable. A study comparing 1287 steroid-treated and no-steroid-treated patients in Hong Kong showed that corticosteroid groups had a lower crude death rate.2 However, a retrospective cohort study of SARS patients showed adverse outcomes (either ICU admission or mortality) following corticosteroid therapy.3 Early treatment of hydrocortisone in SARS patients was associated with a higher subsequent plasma viral load.4 Similarly, a delayed clearance of viral RNA from the respiratory tract was also observed in MERS patients with corticosteroid treatment.5 It seems that by reducing the inflammatory response, corticosteroids also reduce the rest of the immune response and prolong the viral load. Moreover, a meta-analysis synthesized from 10 trials suggested that higher cumulative doses and longer treatment durations of corticosteroids are more likely to develop osteonecrosis in SARS patients.6
In view of no unique reason existing to expect that COVID-19 patients will benefit from corticosteroids, and they might be more likely to be harmed with such treatment, a recent review in The Lancet suggested that corticosteroids should not be used for the treatment of COVID-19-induced lung injury or shock outside of a clinical trial.7 Based on the fact of lack of effectiveness and possible harm, WHO advises against the use of corticosteroids for COVID-19 unless they are indicated for another reason.8
There are, however, study results from several reports demonstrating that the timing, dosage, and duration of corticosteroid therapy are critical if this intervention is to be beneficial in patients.2,9 In a systematic review and meta-analysis including 15 studies published since 2002 and a total of 5,270 patients infected with SARS-CoV, MERS-CoV or SARS-CoV-2, it is suggested that moderate corticosteroids can be used in patients with severe conditions to suppress the immune response and reduce symptoms.10
A UK-based clinical trial RECOVERY (Randomised Evaluation of COVid-19 thERapY) and a global REMAP-CAP trial collaborated together to test the effectiveness of dexamethasone in critically ill patients.11
6. Favipiravir
Favipiravir (Avigan®, FUJIFILM Toyama Chemical Co., Ltd., Tokyo, Japan) is an approved influenza antiviral drug. It is a purine nucleic acid analogue and broad spectrum inhibitor of RNA-dependent RNA polymerase (RdRp) associated with viral replication. As the drug specifically blocks RNA polymerase, the mechanism is expected to have an antiviral effect on SARS-CoV-2 as this is a single-stranded RNA virus like the influenza virus.12 Favipiravir has molecular mechanical activity similar to Remdesivir. While Remdesivir is intended for use in the most severe cases of COVID-19 and reduces their recovery time, favipiravir is tested in the hope that it may help a wider range of patients.
Ebola patients treated with favipiravir showed a trend toward improved survival.13 A retrospective analysis showed a higher overall survival rate and longer average survival time on Ebola patients with additional favipiravir treatment, in comparison with patients with the WHO-recommended supportive therapy. In addition, a higher percentage of Ebola patients who received favipiravir treatment had a more than 100-fold viral load reduction.14
A clinical trial (ChiCTR2000029600) conducted in Shenzhen recruiting 80 patients showed that 35 patients in the favipiravir arm demonstrated significantly shorter viral clearance time, compared with the 45 patients in the control arm (median 4 days vs. 11 days). X-ray chest image confirmed a higher rate of improvement in the favipiravir arm.15 For ordinary patients with COVID-19, the 7-day clinical recovery rate increased from 55.86% to 71.43% with favipiravir treatment. The time of fever reduction and cough relief also decreased significantly.16
The drug is currently in phase 3 development by the original manufacturer (NCT04358549).17 It may be added to the trial SOLIDARITY later by WHO.
Although the using of favipiravir for COVID-19 treatment sounds promising, the Health Minister of Japan, Katsunobu Kato, revealed on May 26 that his ministry has given up on the government's end-May target for approving the drug for the treatment of COVID-19, as no sufficient data to support its efficacy are yet available.18 In fact, favipiravir has a risk for teratogenicity and embryotoxicity.19 The mechanism that makes the drug effective against viruses also makes it destructive to fetuses with rapid cell growth.
7. Interferon beta (e.g. Betaferon (INF-β1b), Rebif (INF-β1a))
Human recombinant interferon beta (INF-β) was originally developed for chronic obstructive pulmonary disorder. Subcutaneous injections of INF-β have been used for the treatment of multiple sclerosis for more than 20 years.20 The human body naturally produce INF-β as a defensive response to viruses.21 It is involved in regulating inflammation in the body and is known to improve the lung's condition and enhance the lung's ability to fight viral infections. A decrease in INF-β production is directly linked to increased susceptibility of people to develop severe respiratory diseases resulting from viral infections; SARS-CoV-2 infection can suppress the INF-β production in the body.22
Interferon beta has shown antiviral effects in vitro and in marmosets infected with MERS.23-26 However, the molecule generally failed to show significant improvement on humans with MERS and SARS infection.27 On the other hand, a recent in vitro study showed that human recombinant INF-β1a inhibits SARS-CoV-2 virus load in cultured cells, at concentrations that are clinically achievable in patients, demonstrating the therapeutic potential of the molecules against COVID-19.28 According to the researcher of the study, "the data may provide an explanation, at least in part, to the observation that approximately 80% of patients actually develop mild symptoms and recover. It is possible that many of them are able to mount IFN-β-mediated innate immune response upon SARS-CoV-2 infection, which helps to limit virus infection/dissemination at an early stage of disease."
The timing for INF-β administration and the application of the molecules to the right people is critical. An in vivo study demonstrated that INF-β administration shortly after infection protected mice from lethal MERS-CoV infection, by inhibiting virus replication and inflammatory cytokine production. On the other hand, delayed administration caused the failure to inhibit viral replication and had adverse events.29 It is also important to apply INF-β treatment to patients only if they don't have comorbidities.30,31
Due to its unspecific antiviral effects, the molecule is often evaluated, usually in combination with other drugs, before specific treatments are developed. For example, a combination of IFN-β with lopinavir/ritonavir was used against MERS-CoV and showed improvement in pulmonary function.32
In clinical trials for COVID-19 treatment, IFN-β is usually used in combination with lopinavir/ritonavir. Subcutaneous IFN-β1a in combination with lopinavir/ritonavir is being tested in the WHO global megatrial Solidarity.33 Subcutaneous IFN-β1b in combination with lopinavir/ritonavir and ribavirin was also tested in other clinical trials such as the open-label one performed in Hong Kong (NCT04276688), for the treatment of COVID-19.34 The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days) than the control group (12 days).
An inhaled form of IFN-β1a, called SNG001, produced by Synairgen, is also being tested in a placebo-controlled trial led by Tom Wilkinson at the University of Southampton. The trial will use the drug much earlier in the course of the illness, to find out if the drug can protect the lungs and prevent the development of the severe lower respiratory tract illness.35 The participants of the trial will receive either SNG001 or placebo, inhaled once daily for 14 days in their homes. Their general medical condition, levels of breathlessness, cough and sputum (mucus from the lungs) will be recorded every day, along with any safety information.
References
1. L.K. So, A.C. Lau, L.Y. Yam, et al. Development of a standard treatment protocol for severe acute respiratory syndrome. Lancet. 2003; 361: 1615-1617.
2. Y.C. Yam, C.W. Lau, Y.L. Lai, et al. Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong. Journal of Infection. (2007) 54, 28-39.
3. T.W. Auyeung, S.W. Lee, W.K. Lai, et al. The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study. J Infect. (2005) 51(2):98-102.
4. N. Lee, K.C. Chan, S. Hui, et al. Effects of early corticosteroid treatment on plasma SARS-associatedCoronavirusRNA concentrations in adult patients. Journal of Clinical Virology, 31 (2004) 304-309.
5. Y.M. Arabi, Y. Mandourah, F. Al-Hameed, et al. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome. Am J Respir Crit Care Med. 2018; 197: 757-767.
6. R. Zhao, H. Wang, X. Wang, et al. Steroid Therapy and the Risk of Osteonecrosis in SARS Patients: A Dose-Response Meta-Analysis. Osteoporos Int, 2017 Mar;28(3):1027-1034.
7. C.D. Russell, J.E. Millar & J.K. Baillie. Lancet. 2020; 395 (10223): 473-475.
8. Clinical management of COVID-19. Interim guidance, 27th May, 2020. World Health Organization.
9. Y. Wang, W.W. Jiang, Q. He, et al. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. MedRxiv, doi: https://doi.org/10.1101/2020.03.06.20032342
10. Z.W. Yang, J.L. Liu, Y.J. Zhou, et al. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect. 2020 Apr 10;S0163-4453(20)30191-2.
11. "Coordination of RECOVERY and REMAP-CAP trials" https://www.recoverytrial.net/files/professional-downloads/coordination-of-recovery-and-remap-cap.pdf
12. Y. Furuta, T. Komeno, & T. Nakamura. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 93, 449-463 (2017).
13. D. Sissoko, C. Laouenan, E. Folkesson, 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 Mar 1;13(3):e1001967.
14. C.Q. Bai, J.S. Mu, D. Kargbo,et al. Clinical and virological characteristics of Ebola virus disease patients treated with favipiravir (T-705)-Sierra Leone, 2014. Clin. Infect. Dis. 63, 1288-1294 (2016).
15. Q. Cai, M. Yang, D. Liu, et al. Experimental treatment with Favipiravir for COVID-19: an open-label control study. Engineering. https://doi.org/10.1016/j.eng.2020.03.007
16. C. Chen, Y. Zhang, J. Huang, et al. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. bioRxiv preprint. https://doi.org/10.1101/2020.03.17.20037432
17. "Fujifilm commences Phase III trial of Avigan for Covid-19" Clinial Trials Area news. 1st April, 2020. https://www.clinicaltrialsarena.com/news/fujifilm-avigan-covid-19-trial-japan/)
18. "Japan approval for Avigan to treat COVID-19 delayed" The Pharma Letter. https://www.thepharmaletter.com/article/japan-approval-for-avigan-to-treat-covid-19-delayed
19. T. Nagata, A.K. Lefor, M. Hasegawa, et al. Favipiravir: A New Medication for the Ebola Virus Disease Pandemic. Disaster Med Public Health Prep, 2015 Feb;9(1):79-81.
20. D. Jakimovski, C. Kolb, M. Ramanathan, et al. Interferon ? for multiple sclerosis. Cold Spring Harb. Perspect. Med., 8 (2018), pp. 1-20
21. Y.J. Liu. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23 (2005), pp. 275-306.
22. E. Sallard, F.X. Lescure, Y. Yazdanpanah, et al. Type 1 interferons as a potential treatment against COVID-19. Antivir Res. 2020; 178:104791.
23. L.E. Hensley, E.A. Fritz, P.B. Jahrling, et al. INF-?1a and SARS coronavirus replication. Emerg. Infect. Dis., 10 (2004), pp. 317-319.
24. J.F.W. Chan, K.H. Chan, R.Y.T. Kao, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J. Infect. 67 (2013), pp. 606-616.
25. B.J. Hart, J. Dyall, E. Postnikova, et al. Interferon-? and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J. Gen. Virol., 95 (2014), pp. 571-577.
26. J.F. Chan, Y. Yao, M.L. Yeung, et al. Treatment with lopinavir/ritonavir or interferon-beta1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis, 2015 Dec 15;212(12):1904-1913.
27. L.J. Stockman, R. Bellamy and P. Garner. SARS: systematic review of treatment effects. PLoS Med., 3 (2006), pp. 1525-1531.
28. E. Mantlo, N. Bukreyeva, J. Maruyama, et al. Antiviral Activities of Type I Interferons to SARS-CoV-2 Infection. Antiviral Res. 2020 Apr 29;179:104811.
29. R. Channappanavar, A.R. Fehr, J. Zheng, et al. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J. Clin. Invest., 129 (2019), pp. 3625-3639.
30. J.A. Al-Tawfiq, H. Momattin, J. Dib, et al. Ribavirin and ingerferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an obsevtional study. Int. J. Infect. Dis. 20 (2014), pp. 42-46.
31. S. Shalhoub, F. Farahat, A. Al-Jiffri, et al. INF-a2a or INF-b1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study.J. Antimicrob. Chemother., 70 (2015), pp. 2129-2132.
32. T.P. Sheahan, A.C. Sims, S.R. Leist, et al. Comparative therapeutic efficacy of Remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020 Jan 10;11(1):222.
33. ""Solidarity" clinical trial for COVID-19 treatments." World Health Organization. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
34. F.N. Hung, K.C. Lung, Y.K. Tso, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet, 2020, Vol.395, 10238, p.1695-1704.
35. "University-led COVID19 drug trial expands into home testing" Medical Express. 27th May, 2020. https://medicalxpress.com/news/2020-05-university-led-covid19-drug-trial-home.html
No comments:
Post a Comment