Review of the Literature of Remdesivir Use for COVID-19

Coronaviruses are a class of enveloped viruses with a single-stranded RNA genome that infects animals and humans. There are many types of coronaviruses that cause infections exemplified by the common cold, severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome-related coronavirus (MERS), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen associated with COVID-19. (1) The clinical development of remdesivir, with a confirmed capability to inhibit SARS-CoV-2 replication, supports the evaluation for COVID-19 treatment (1).

Remdesivir (GS-5734) was developed by Gilead Sciences and arose from an alliance of research with the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) (1). This collaborative research was to identify therapeutic agents for treating RNA-based viruses that could lead to potential global pandemic such as anticipated with the Ebola virus outbreak of 2014(1). Remdesivir (GS-5734), is a prodrug that is metabolized within cells into an alanine metabolite, further processed into the monophosphate derivative, and eventually into the active nucleoside triphosphate derivative responsible for the inhibition of viral replication through the production of a delayed chain reaction (1).

On January 20, 2020, a patient who reported to an urgent care center in Snohomish County, Washington was confirmed as the first positive case of COVID-19 in the USA.(1, 6) On the seventh day of hospitalization and after worsening clinical status, the patient was given IV remdesivir under compassionate use access (Gilead Sciences), with no adverse events observed upon infusion.(6) The patient’s clinical condition improved the next day, although concurrent treatment with acetaminophen, ibuprofen, guaifenesin, vancomycin, cefepime, and supplemental oxygen confound the direct interpretation of remdesivir’s impact. This single case report of COVID-19 suggested the recovery of a patient probably due to the administration of remdesivir (1, 2).

Subsequently, 12 patients were confirmed to be infected with SARS-CoV-2 between January 20, 2020, and February 5, 2020. (7) Of these 12 patients, seven were hospitalized and three received remdesivir (compassionate use) upon worsening clinical disease. Treatment was continued for 4–10 days with 200 mg IV on the first day and 100 mg each following day. Following the initial dose, all patients experienced “transient gastrointestinal symptoms, including nausea, vomiting, gastroparesis, or rectal bleeding,” although treatment was continued until improvement in respiratory symptoms, with all 12 patients reporting symptom resolution by February 22, 2020.(7) The small sample size and lack of controlled randomization preclude analysis of clinical efficacy or safety. Another study of compassionate-use remdesivir, reported clinical improvement in 68% of the 53 recruited patients who had severe COVID-19 (2,4).

To determine the most effective treatments for COVID-19 and ensure sufficient power to observe definitive results, the World Health Organization (WHO) announced the SOLIDARITY clinical trial, a four-arm trial comparing remdesivir, lopinavir/ritonavir, lopinavir/ritonavir with interferon-β1a, and chloroquine or hydroxychloroquine (1). As of the end of March 2020, there were over 70 countries committed to participating, and the preliminary results are pending.

On there are over 30 studies listed looking at remdesivir for COVID-19 infections with at least seven RCTs initiated, aiming to evaluate the benefit and harm effects of remdesivir for COVID-19 patients (2). Of note, one study was suspended and one study terminated in China since the outbreak was controlled and there were no patients to enroll into either study, and one study is specifically targeting pediatric patients.

Another study that has been completed was a double-blind, randomized, placebo-controlled trial of IV remdesivir in COVID-19 hospitalized adults with lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection control purposes. This study involved 1063 patients who underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). This study concluded that remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection (5).

While there remain many questions about the safety of remdesivir for COVID-19, there remains promise in the treatment of COVID-19. We have learned that remdesivir likely is effective in at least reducing the number of hospitalized days for those patients with lower respiratory infections and potentially may allow for resolution of respiratory symptoms. Additionally, according to the June 2020, STAT Biotech newsletter, Gilead released the price for all government facilities to pay $2,340 for a 5-day course and Medicaid will pay about a third more at $3,120 with developing countries receiving a much lower cost.

  1. Eastman, Richard T et al. “Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19.” ACS central science vol. 6,5 (2020): 672-683. doi:10.1021/acscentsci.0c00489
  2. Li Z, Wang X, Cao D, Sun R, Li C, Li G. Rapid review for the anti-coronavirus effect of remdesivir, Drug Discoveries & Therapeutics. 2020; 14(2):73-76. DOI: 10.5582/ddt.2020.01015
  3. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020; 382:929-936.
  4. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A,Feldt T, Green G, Green ML, Lescure FX, Nicastri E, Oda R, Yo, K, Quiros-Roldan E, Studemeister A, Redinski J, Ahmed S, Bernett J, Chelliah D, Chen D, Chihara S, Cohen SH, Cunningham J, D’Arminio Monforte A, Ismail S, Kato H, Lapadula G, L’Her E, Maeno T, Majumder S, Massari M, Mora-Rillo M, Mutoh Y, Nguyen D, Verweij E, Zoufaly A, Osinusi AO, DeZure A, Zhao Y, Zhong L, Chokkalingam A, Elboudwarej E, Telep L, Timbs L, Henne I, Sellers S, Cao H, Tan SK, Winterbourne L, Desai P, Mera R, Gaggar A, Myers RP, Brainard DM, Childs R and Flanigan T: Compassionate use of remdesivir for patients with severe covid-19. N Engl J Med, 2020. PMID: 32275812. DOI: 10.1056/NEJMoa2007016
  5. Beigel, John H et al. “Remdesivir for the Treatment of Covid-19 - Preliminary Report.” The New England journal of medicine, NEJMoa2007764. 22 May. 2020, doi:10.1056/NEJMoa2007764
  6. Holshue M. L.; et al. First Case of 2019 Novel Coronavirus in the United States. N. Engl. J. Med. 2020, 382 (10), 929–936. 10.1056/NEJMoa2001191.
  7. Kujawski S. al.First 12 patients with coronavirus disease 2019 (COVID-19) in the United States. MedRxiv, 2020,10.1101/2020.03.09.20032896.
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