1.     Remdesivir (RDV)

Remdesivir (abbreviation: RDV) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of single stranded RNA virus families including Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae (Brown 2019, Sheehan 2017), through the targeting of the viral RNA dependent RNA polymerase (RdRp) (Cho 2012, Agostini 2018). The drug was initially reported to have in vivo antiviral efficacy against Ebola virus in nonhuman primates (Warren 2016) and it was used during the Kivu Ebola epidemic. However, a randomized controlled trial showed that remdesivir was significantly less effective than the single monoclonal antibody mAb114, or the triple monoclonal antibody REGN-EB3 (Mulangu 2019).

The first Remdesivir COVID-19 studies showed mixed results. Findings of a compassionate use program (Grein 2020) have been judged inconclusive and are being interpreted with caution (Hoffmann 2020, xxx, xxx, xxx, xxx). Results of the first randomised, double-blind, placebo-controlled, multicenter trial reported that RDV use was not associated with a difference in time to clinical improvement (Wang Y 2020). Only patients who received the drug within the first 10 days after the appearance of symptoms seemed to have a faster time to clinical improvement; however, this was statistically not significant.

On 1 May 2020, the FDA granted RDV emergency use authorization for treatment of COVID-19. The drug will still need formal approval if the manufacturer provides additional data of the drug’s safety and effectiveness.

Although Remdesivir is far from being a Penicillin-like watershed in medicine, some studies indicate that SARS-2-CoV could be amenable to drug treatment. More potent drugs are urgently needed.

Brand Name: N/A ™

Drug Class: Nucleotide Analogs

Manufacturer: Gilead Sciences

N/A™ vials: 100 mg.

Remdesivir can be administered only by intravenous injection.

Indications: COVID-19.

Dose used during trials: Loading dose of 200 mg IV on day 1, followed by 100 mg IV daily for 9 days (Wang Y 2020).

Side effects: Typical side effects include nausea and vomiting, elevated transaminases and infusion site reactions (Mehta 2020). Signs and symptoms of infusion‐related reactions may include low blood pressure, nausea, vomiting, sweating, and shivering (FDA 2020).

Interactions: RDV is not believed to affect other medications; however, some drugs may affect RDV and should probably not be coadministered: rifampicin, rifapentine, carbamazepine, phenobarbital, phenytoin, primidone, St John’s wort, may affect RDV. For more details, consult information provided by the Liverpool Drug Interactions Group at www.covid19-druginteractions.org.

Comments/Warnings: It is unknown whether RDV is safe during pregnancy and whether is passes into breast milk.

Internet sources: xxx

References

Agostini ML, Andres EL, Sims AC, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018 Mar 6;9(2). pii: mBio.00221-18. PubMed: https://pubmed.gov/29511076. Full-text: https://doi.org/10.1128/mBio.00221-18

Brown AJ, Won JJ, Graham RL, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 2019 Sep;169:104541. PubMed: https://pubmed.gov/31233808. Full-text: https://doi.org/10.1016/j.antiviral.2019.104541

Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10. PubMed: https://pubmed.gov/32275812. Full-text: https://doi.org/10.1056/NEJMoa2007016

FDA. Frequently Asked Questions on the Emergency Use Authorization for Remdesivir for Certain Hospitalized COVID‐19 Patients”. U.S. Food and Drug Administration (FDA). 1 May 2020. https://www.fda.gov/media/137574/download. Retrieved 3 May 2020.

Mehta N, Mazer-Amirshahi M, Alkindi N, Ali Pourmand. Pharmacotherapy in COVID-19; A narrative review for emergency providers. Am J Emerg Med. 2020 Apr 15. pii: S0735-6757(20)30263-1. PubMed: https://pubmed.gov/32336586. Full-text: https://doi.org/10.1016/j.ajem.2020.04.035

Mulangu S, Dodd LE, Davey RT Jr, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019 Dec 12;381(24):2293-2303. PubMed: https://pubmed.gov/31774950. Full-text: https://doi.org/10.1056/NEJMoa1910993

Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017 Jun 28;9(396). pii: 9/396/eaal3653. PubMed: https://pubmed.gov/28659436. Full-text: https://doi.org/10.1126/scitranslmed.aal3653

Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016 Mar 17;531(7594):381-5. PubMed: https://pubmed.gov/26934220. Full-text: https://doi.org/10.1038/nature17180

Cho A, Saunders OL, Butler T, et al. Synthesis and antiviral activity of a series of 1´-substituted 4-aza-7,9-dideazaadenosine C-nucleosides. Bioorg Med Chem Lett. 2012 Apr 15;22(8):2705-7. PubMed: https://pubmed.gov/22446091. Full-text: https://doi.org/10.1016/j.bmcl.2012.02.105

Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, April 29, 2020. Full-text: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext

2.     Lopinavir

Lopinavir is an HIV protease inhibitors (PI) first approved in 2000. It is today out of fashion for HIV treatment because of side effects (diarrhea, dyslipidemia), interactions and inconvenient dosage (high number of pills). Today, better HIV regimes are available (Madruga 2007, Riddler 2008, De Meyer 2009).

To achieve appropriate plasma levels, lopinavir must be boosted with another PI called ritonavir (usually indicated by “/r”: lopinavir/r. As with all HIV PIs, one must be aware of drug-drug interactions. Ritonavir is a strong pharmacoenhancer and cannot be used with a variety of other drugs (see the contraindications below). For example, tacrolimus has to be reduced by 10-100 fold to maintain concentration within the therapeutical range (Bartiromo 2020).

For lopinavir/r, at least two case-control studies on SARS (Chan 2003, Chu 2004) and one prophylactic study on MERS (Park 2019) indicated a beneficial effect. When used 10 to 17 days after onset of COVID-19, a randomized open-lable trial in 199 adults hospitalized with severe illness did not find any clinical benefit beyond standard care (Cao 2020). There is one retrospective study on 280 cases in which early initiation of lopinavir/r and/or ribavirin showed some benefits (Wu 2020).

Lopinavir/r will continue to be tested in WHO’s huge SOLIDARITY trial. There is currently no reason to believe that the drug will have an important impact on the COVID-19 pandemic.

Brand Name: Kaletra™

Drug Class: Protease inhibitor

Manufacturer: AbbeVie. Generic drugs are available.

Kaletra® film-coated tablets with 200 mg lopinavir + 50 mg ritonavir.

Kaletra® film-coated tablets with 100 mg lopinavir + 25 mg ritonavir.

Kaletra® solution with 80 mg lopinavir + 20 mg ritonavir per ml.

Indications: HIV infection, adults and children over 2 years.

Dose: 1x 4 tablets (800 mg lopinavir / 200 mg ritonavir) regardless of meals.

Side effects: especially diarrhea, nausea, dyslipidemia. Abdominal pain, asthenia, headache, vomiting and, particularly in children, rash, are less frequent.

Note: The solution contains ethanol, it should be kept in the refrigerator.

Interactions: Drugs that are metabolised by CYP3A or CYP2D6 are contraindicated: Flecainide, propafenone, terfenadine, ergotamine, cisapride, midazolam, triazolam. Rifampicin and St. John’s wort reduce the effectiveness of lopinavir. Be careful with lovastatin, simvastatin (rhabdomyolysis), carbamazepine, phenobarbital, phenytoin or sildenafil (drop in blood pressure), amiodarone, marcumar, lidocaine, tricyclic antidepressants, quinidine, cyclosporin, tacrolimus. Measure serum levels in patients with impaired liver function, transaminase elevations. Sometimes, methadone dosage needs to be increased.

References

Bartiromo M, Borchi B, Botta A, et al. Threatening drug-drug interaction in a kidney transplant patient with Coronavirus Disease 2019 (COVID-19). Transpl Infect Dis. 2020 Apr 12. PubMed: https://pubmed.gov/32279418. Full-text: https://doi.org/10.1111/tid.13286

Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 Mar 18. PubMed: https://pubmed.gov/32187464. Full-text: https://doi.org/10.1056/NEJMoa2001282

Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003 Dec;9(6):399-406 PubMed: https://pubmed.gov/14660806. Full-text: https://www.hkmj.org/PubMeds/v9n6/399.htm

Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004 Mar;59(3):252-6. PubMed: https://pubmed.gov/14985565. Full-text: https://doi.org/10.1136/thorax.2003.012658

De Meyer S, Lathouwers E, Dierynck I, et al. Characterization of virologic failure patients on darunavir/ritonavir in treatment-experienced patients. AIDS. 2009 Sep 10;23(14):1829-40. PubMed: https://pubmed.gov/19474650. Full-text: https://doi.org/10.1097/QAD.0b013e32832cbcec

Lim J, Jeon S, Shin HY, et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR. J Korean Med Sci. 2020 Feb 17;35(6):e79. PubMed: https://pubmed.gov/32056407. Full-text: https://doi.org/10.3346/jkms.2020.35.e79

Liu F, Xu A, Zhang Y, et al. Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression. Int J Infect Dis. 2020 Mar 12. pii: S1201-9712(20)30132-6. PubMed: https://pubmed.gov/32173576. Full-text: https://doi.org/10.1016/j.ijid.2020.03.013

Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. 2007 Jul 7;370(9581):49-58. PubMed: https://pubmed.gov/17617272. Full-text:

Park SY, Lee JS, Son JS, et al. Post-exposure prophylaxis for Middle East respiratory syndrome in healthcare workers. J Hosp Infect. 2019 Jan;101(1):42-46. PubMed: https://pubmed.gov/30240813. Full-text: https://doi.org/10.1016/j.jhin.2018.09.005

Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008 May 15;358(20):2095-106. PubMed: https://pubmed.gov/18480202. Full-text: https://doi.org/10.1056/NEJMoa074609

Sheahan TP, Sims AC, Leist SR, 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. PubMed: https://pubmed.gov/31924756. Full-text: https://doi.org/10.1038/s41467-019-13940-6

Wu J, Li W, Shi X, et al. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID-19). J Intern Med. 2020 Mar 27. PubMed: https://pubmed.gov/32220033. Full-text: https://doi.org/10.1111/joim.13063

Zhu Z, Lu Z, Xu T, et al. Arbidol Monotherapy is Superior to Lopinavir/ritonavir in Treating COVID-19. J Infect. 2020 Apr 10. pii: S0163-4453(20)30188-2. PubMed: https://pubmed.gov/32283143. Full-text: https://doi.org/10.1016/j.jinf.2020.03.060

 

Favipiravir

References

Beigel JH, Nam HH, Adams PL, et al. Advances in respiratory virus therapeutics – A meeting report from the 6th isirv Antiviral Group conference. Antiviral Res. 2019 Jul;167:45-67. PubMed: https://pubmed.gov/30974127. Full-text: https://doi.org/10.1016/j.antiviral.2019.04.006

Cai Q, Yang M, Liu D, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing). 2020 Mar 18. pii: S2095-8099(20)30063-1. PubMed: https://pubmed.gov/32346491. Full-text: https://doi.org/10.1016/j.eng.2020.03.007

Chen C, Huang J, Cheng Z, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. Posted March 27, medRxiv. Full-text: https://doi.org/10.1101/2020.03.17.20037432

Choy KT, Wong AY, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020 Apr 3;178:104786. PubMed: https://pubmed.gov/32251767. Full-text: https://doi.org/10.1016/j.antiviral.2020.104786

Costanzo M, De Giglio MAR, Roviello GN. SARS-CoV-2: Recent Reports on Antiviral Therapies Based on Lopinavir/Ritonavir, Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and Other Drugs for the Treatment of the New Coronavirus Curr Med Chem. 2020 Apr 16. pii: CMC-EPUB-105865. PubMed: https://pubmed.gov/32297571. Full-text: https://doi.org/10.2174/0929867327666200416131117

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