Antiviral Agents: What is their use in COVID-19?

Authors: Adeline Dozois, MD (Emergency Medicine Attending, Carolinas Medical Center, Charlotte, NC) and Kathryn T. Kopec, DO (Emergency Medicine Attending, Medical Toxicologist, Carolinas Medical Center, Charlotte, NC) // Reviewed by: Cynthia Santos, MD (@Cynthia Santos); Alex Koyfman, MD (@EMHighAK); Manny Singh, MD (@MPrizzleER); and Brit Long, MD (@long_brit)

Background

As the death toll of COVID-19 rises worldwide, treatment remains limited to supportive measures. Though no specific therapies are currently recommended by the WHO, researchers are actively searching for agents aimed at decreasing disease severity or viral shedding in COVID-19 patients. Antiviral medications have become a main focus of potential treatment options. There are several antiviral drugs that are current targets of investigation for use in SARS-CoV-2: remdesivir, lopinavir-ritonavir, interferon/ribavirin, and favipiravir.


The Medications…

Remdesivir

Remdesivir is a novel antiviral drug developed by Gilead Sciences that is currently under investigation as a treatment for COVID-19. It is a nucleotide analogue RNA polymerase inhibitor, has been previously tested in a limited number of patients with Ebola, SARS, and MERS. In a trial of four investigational drugs against Ebola (remdesivir, ZMapp, MAb114 and REGN-EB3), random assignment to the remdesivir group was terminated early after interim analysis found that mortality was significantly higher in this group than in patients assigned to receive MAb114 and REGN-EB3.1 The drug was shown be effective in prevention and treatment MERS-CoV in primate models.2 Due to the preventative effects of this agent, it has been suggested that remdesivir could be used as a prophylactic medication in healthcare workers and known positive contacts.2 Preliminary studies have demonstrated that remdesivir inhibits SARS-CoV-2 infection in human liver cells.3  A phase 3 clinical trial of this drug is underway in the U.S. for patients with moderate and severe COVID-19 in which participants receive 200mg IV on day one, followed by 100mg IV daily for either a 5 or 10 day course.4–6 Clinical trials are also ongoing in China.7 Limited data and safety information are available for this drug currently. Remdesivir is not commercially available currently, though requests can be made to the FDA for expanded access, also known as “compassionate use”.


Lopinavir-Ritonavir

Lopinavir (LPV) is a protease inhibitor widely used in treatment of HIV, which is often combined with ritonavir (RTV) to increase the half-life of LPV through CYP450 3A4 inhibition. LPV alone typically has poor bioavailability due to rapid metabolism by CYP450 3A4; the addition of RTV competitively inhibits CYP450 3A4, slowing the metabolism of LPV and serving as a “boost” to the plasma concentration of the active drug.8 The compound has successfully been used in the treatment of SARS and MERS-CoV.9 The most robust evidence to date on the use of LPV-RTV comes from a randomized controlled trial of 199 patients with COVID-19, in which the drug failed to demonstrate an improvement against standard care in time to clinical improvement, mortality, or percentage of patients with detectable viral RNA at various time points.10 Also, there were 4 serious gastrointestinal adverse events in the LPV-RTV group, including acute gastritis (2 cases) and lower GI bleeding (2 cases), and none in the standard-care group. This study had a mortality rate of 22.5%, which is significantly higher than the current reported mortality rate in other studies of hospitalized patients with COVID-19.10


Interferon-alpha and Ribavirin

Interferon and ribavirin are among the drugs recommended by the Chinese guidelines for treatment of COVID-19 and have emerged as an interest to U.S. researchers. Interferon-alpha inhibits viral infection by inducing host immune responses. It can be used in the treatment of hepatitis B and C and inhibits infection from respiratory coronaviruses.11 Ribavirin is a guanosine analog that disrupts replication of multiple RNA viruses.12 Both interferon-alpha and ribavirin showed inhibition of SARS-COV-1 (the source of the 2003 SARS epidemic) in vitro.13 Investigations into interferon-alpha treatment stem experience in treatment of the related MERS-CoV.3 Combination of ribavirin and interferon-alpha improved 14-day mortality in critically ill patients, though it did not show an improvement in 28-day mortality rate.12 Later retrospective studies on MERS-CO-V patients did not demonstrate improvement in 90-day mortality or virus clearance.14

A separate trial investigated the effect of interferon-alpha in conjunction with corticosteroids against SARS-CoV-1.11 In this open label study of 22 patients receiving corticosteroids for SARS, the addition of interferon-alpha in nine patients resulted in statistically significant improvement in oxygen saturation, need for supplemental oxygen, and time to 50% resolution of lung radiographic abnormalities.11 The dose recommend by the Chinese guidelines is interferon-alpha is 5 million units by vapor inhalation 2 times per day, if ribavirin is added they recommend 500mg IV 2-3 times per day.3 As of this writing, there are currently six trials registered on ClinicalTrials.gov investigating the effect of interferon therapy.15–20


Favipiravir

Favipiravir is a broad-spectrum viral RNA inhibitor which was initially thought to have activity against influenza.21 It is currently under investigation for COVID-19.22


The Verdict?

  • Currently, there is not adequate data available on the effectiveness or safety of remdesivir, lopinavir/ritonavir, interferon +/- ribavirin, or favipiravir to recommend their use.
  • This is in line with current recommendations from the World Health Organization, the Centers for Disease Control, and the Food and Drug Administration.23
  • These compounds remain drugs to watch as more trials determine their safety and efficacy in the treatment of COVID-19.

 

References/Further Reading:

  1. Mulangu S, Dodd LE, Proschan M, et al. A randomized, controlled trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019;381(24):2293-2303. doi:10.1056/NEJMoa1910993
  2. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci. February 2020:201922083. doi:10.1073/pnas.1922083117
  3. Du B, Qiu HB, Zhan X, et al. [Pharmacotherapeutics for the new coronavirus pneumonia]. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese J Tuberc Respir Dis. 2020;43(3):173-176. doi:10.3760/cma.j.issn.1001-0939.2020.03.005
  4. Study to evaluate the safety and antiviral activity of remdesivir (GS-5734) in participants with severe coronavirus disease (COVID-19). NCT04292899.
  5. Study to evaluate the safety and antiviral activity of remdesivir (GS-5734) in participants with moderate coronavirus disease (COVID-19) compared to standard of care treatment. NCT04292730. https://www.clinicaltrials.gov/ct2/show/NCT04292730.
  6. Expanded access remdesivir (RDV; GS-5734).
  7. Routh J. NIH clinical trial of remdesivir to treat COVID-19 begins. National Institutes of Health. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-remdesivir-treat-covid-19-begins. Accessed March 19, 2020.
  8. van Waterschoot RAB, ter Heine R, Wagenaar E, et al. Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir. Br J Pharmacol. 2010;160(5):1224-1233. doi:10.1111/j.1476-5381.2010.00759.x
  9. Zhang L, Liu Y. Potential interventions for novel coronavirus in China : A systematic review. 2020;(February):479-490. doi:10.1002/jmv.25707
  10. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. 2020:1-13. doi:10.1056/NEJMoa2001282
  11. Loutfy MR, Blatt LM, Siminovitch KA, et al. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. JAMA. 2003;290(24):3222-3228. doi:10.1001/jama.290.24.3222
  12. Omrani AS, Saad MM, Baig K, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis. 2014;14(11):1090-1095. doi:10.1016/S1473-3099(14)70920-X
  13. Stockman LJ, Bellamy R, Garner P. SARS: Systematic Review of Treatment Effects. PLOS Med. 2006;3(9):1-7. doi:10.1371/journal.pmed.0030343
  14. Arabi YM, Shalhoub S, Mandourah Y, et al. Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study. Clin Infect Dis. June 2019. doi:10.1093/cid/ciz544
  15. A Prospective/Retrospective,Randomized Controlled Clinical Study of Interferon Atomization in the 2019-nCoV Pneumonia. https://clinicaltrials.gov/ct2/show/NCT04254874?term=interferon&cond=COVID-19&draw=2&rank=1.
  16. Efficacy and Safety of IFN-α2β in the Treatment of Novel Coronavirus Patients.
  17. Experimental Trial of rhIFNα Nasal Drops to Prevent 2019-nCOV in Medical Staff.
  18. Evaluation of Ganovo (Danoprevir) Combined With Ritonavir in the Treatment of Novel Coronavirus Infection. https://clinicaltrials.gov/ct2/show/NCT04291729?term=interferon&cond=COVID-19&draw=2&rank=4.
  19. Trial of Treatments for COVID-19 in Hospitalized Adults (DisCoVeRy).
  20. Lopinavir/ Ritonavir, Ribavirin and IFN-beta Combination for nCoV Treatment. https://clinicaltrials.gov/ct2/show/NCT04276688?term=interferon&cond=COVID-19&draw=3&rank=11.
  21. Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449-463. doi:10.2183/pjab.93.027
  22. Favipiravir Combined With Tocilizumab in the Treatment of Corona Virus Disease 2019. https://clinicaltrials.gov/ct2/show/NCT04310228?term=favipiravir&cond=covid19&draw=2&rank=2.
  23. Smith T, Prosser T. COVID-19 Drug Therapy – Potential Options. 2020;(Cdc):19-22.

 

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