Author: Himanshu Sadulwad
If one gets infected with COVID-19, not all hope is lost. There are treatment options available to treat the disease based on the severity and the strain which has infected the individual.
Stages of the disease
Before listing the options available for treatment let us first take a look at the different stages through which this disease progresses. The National Institutes of Health (NIH) issued guidelines that classify COVID-19 into five distinct types.
Asymptomatic or presymptomatic infection:
Individuals with positive SARS-CoV-2 test without any clinical symptoms consistent with COVID-19
Mild illness:
Individuals who have any symptoms of COVID-19 such as fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, anosmia (loss of smell), or dysgeusia (altered taste) but without shortness of breath or abnormal chest imaging.
Moderate illness:
Individuals who have clinical symptoms or radiologic evidence of lower respiratory tract disease and who have oxygen saturation (SpO2) ≥ 94% on room air.
Severe illness:
Individuals who have (SpO2) ≤ 94% on room air; a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, (PaO2/FiO2) <300 with marked tachypnea with respiratory frequency >30 breaths/min or lung infiltrates >50%.
Critical illness:
Individuals who have acute respiratory failure, septic shock, and/or multiple organ dysfunction. Patients with severe COVID-19 illness may become critically ill with the development of acute respiratory distress syndrome (ARDS) which tends to occur approximately one week after the onset of symptoms.
Medicines to treat COVID-19
Currently, a variety of therapeutic options are available that include antiviral drugs, anti-SARS-CoV-2 monoclonal antibodies, anti-inflammatory drugs, immunomodulators agents are available under FDA issued Emergency Use Authorization( EUA) or being evaluated in the management of COVID-19.
The clinical utility of these treatments is specific and is based on the severity of illness or certain risk factors. The clinical course of the COVID-19 illness occurs in 2 phases, an early phase when SARS-CoV-2 replication is greatest before or soon after the onset of symptoms.
Antiviral medications and antibody-based treatments are likely to be more effective during this stage of viral replication. The later phase of the illness is driven by a hyperinflammatory state induced by the release of cytokines and the coagulation system’s activation that causes a prothrombotic state. Anti-inflammatory drugs such as corticosteroids, immunomodulating therapies, or a combination of these therapies may help combat this hyperinflammatory state than antiviral therapies.
Antiviral therapies:
Molnupiravir
Named after the Norse God Thor's hammer Mjölnir, molnupiravir is a directly acting broad-spectrum oral antiviral agent acting on the RdRp enzyme was initially developed as a possible antiviral treatment for influenza, alphaviruses including Eastern, Western, and Venezuelan equine encephalitic viruses. Based on meta-analysis of available phase 1-3 studies, molnupiravir was noted to demonstrate a significant reduction in hospitalization and death in mild COVID-19 disease. Results from a phase 3 double-blind randomized placebo controlled trial reported that early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19.
Paxlovid
It consists of ritonavir in combination with nirmatrelvir. It is an oral combination pill of two antiviral agents which on an interim analysis of phase 2-3 data, found that the risk of COVID-19 related hospital admission or all-cause mortality was 89% lower in the paxlovid group when compared to placebo when started within three days of symptom onset. FDA approved Paxlovid for patients with mild to moderate disease.
Remdesivir
It is a broad-spectrum antiviral agent that previously demonstrated antiviral activity against SARS-CoV-2 in vitro.Based on results from three randomized, controlled clinical trials that showed that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with mild-to-severe COVID-19, the FDA approved remdesivir for clinical use in adults and pediatric patients. However, results from the WHO SOLIDARITY Trial conducted at 405 hospitals spanning across 40 countries involving 11,330 inpatients with COVID-19 who were randomized to receive remdesivir (2750) or no drug (4088) found that remdesivir had little or no effect on overall mortality, initiation of mechanical ventilation, and length of hospital stay.
There is no data available regarding the efficacy of remdesivir against the new SARS-CoV-2 variants; however, acquired resistance against mutant viruses is a potential concern.
Hydroxychloroquine and chloroquine
These were proposed as antiviral treatments for COVID-19 initially during the pandemic. However, data from randomized control trials evaluating the use of hydroxychloroquine with or without azithromycin in hospitalized patients did not improve the clinical status or overall mortality compared to placebo. Data from randomized control trials of hydroxychloroquine used as postexposure prophylaxis did NOT prevent SARS-CoV-2 infection or symptomatic COVID-19 illness.
Lopinavir/Ritonavir
It is an FDA-approved combo therapy for the treatment of HIV and was proposed as antiviral therapy against COVID-19 during the early onset of the pandemic. Data from a randomized control trial that reported NO BENEFIT was observed with lopinavir-ritonavir treatment compared to standard of care in patients hospitalized with severe COVID-19. It is currently not indicated for the treatment of COVID-19 in hospitalized and nonhospitalized patients.
Ivermectin
It is an FDA-approved anti-parasitic drug used worldwide in the treatment of COVID-19 based on an in vitro study that showed inhibition of SARS-CoV-2 replication. A single-center double-blind, randomized control trial involving 476 adult patients with mild COVID-19 illness was randomized to receive ivermectin 300 mcg/kg body weight for five days or placebo did NOT achieve significant improvement or resolution of symptoms. Ivermectin is currently not indicated for the treatment of COVID-19 in hospitalized and nonhospitalized patients.
Anti-SARS-CoV-2 Neutralizing Antibody Products:
Individuals recovering from COVID-19 develop neutralizing antibodies against SARS-CoV-2, and the duration of how long this immunity lasts is unclear. Nevertheless, their role as therapeutic agents in the management of COVID-19 is extensively being pursued in ongoing clinical trials.
Convalescent Plasma therapy
This therapy was evaluated during the SARS, MERS, and Ebola epidemics; however, it lacked randomized control trials to back its actual efficacy. The FDA approved convalescent plasma therapy under a EUA for patients with severe life-threatening COVID-19. Although it appeared promising, data from multiple studies evaluating the use of convalescent plasma in life-threatening COVID-19 has generated mixed results.
REGN-COV2
It is an antibody cocktail containing two noncompeting IgG1 antibodies (casirivimab and imdevimab) that target the RBD on the SARS-CoV-2 spike protein that has been shown to decrease the viral load in vivo, preventing virus-induced pathological sequelae when administered prophylactically or therapeutically in non-human primates. Results from an interim analysis of 275 patients from an ongoing double-blinded trial involving non hospitalized patients with COVID-19 who were randomized to receive placebo, reported that the REGN-COV2 antibody cocktail reduced viral load compared to placebo. This interim analysis also established the safety profile of this cocktail antibody, similar to that of the placebo group.
Bamlanivimab and Etesevimab
These are potent anti-spike neutralizing monoclonal antibodies. Bamlanivimab is a neutralizing monoclonal antibody derived from convalescent plasma obtained from a patient with COVID-19. Like REGN-COV2, it also targets the RBD of the spike protein of SARS-CoV-2 and has been shown to neutralize SARS-CoV-2 and reduce viral replication in non-human primates. In Phase 2 of the BLAZE-1 trial, bamlanivimab/etesevimab was associated with a significant reduction in SARS-CoV-2 viral load compared to placebo
Sotrovimab
It is a potent anti-spike neutralizing monoclonal antibody that demonstrated in vitro activity against all the four VOCs. Results from a preplanned interim analysis(not yet peer-reviewed) of the multicenter, double-blind placebo-controlled Phase 3, demonstrated that one dose of sotrovimab (500 mg) reduced the risk of hospitalization or death by 85% in high-risk non hospitalized patients with mild to moderate COVID-19 compared with placebo.
Immunomodulatory Agents:
Corticosteroids
Severe COVID-19 is associated with inflammation-related lung injury driven by the release of cytokines characterized by an elevation in inflammatory markers. The Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial, which included hospitalized patients with clinically suspected or laboratory-confirmed SARS-CoV-2 who were randomly assigned to received dexamethasone or usual care showed that the use of dexamethasone resulted in lower 28-day mortality in patients who were on invasive mechanical ventilation or oxygen support but not in patients who were not receiving any respiratory support.
Interferon-ß-1a
Interferons are cytokines that are essential in mounting an immune response to a viral infection, and SARS-CoV-2 suppresses its release in vitro.[123] However, previous experience with IFN- β-1a in acute respiratory distress syndrome (ARDS) has not benefited. Currently, there is no data available regarding the efficacy of interferon β-1a on the four SARS-CoV-2 VOCs Alpha (B.1.1.7), Beta (B.1.351), Gamma(P1), and Delta (B.1.617.2). Given the insufficient and small amount of data regarding this agent’s use and the relative potential for toxicity, this therapy is NOT recommended to treat COVID-19 infection.
Interleukin (IL)-1 Antagonists
Anakinra is an interleukin-1 receptor antagonist that is FDA approved to treat rheumatoid arthritis. Its off-label use in severe COVID-19 was assessed in a small case-control study trial based on the rationale that the severe COVID-19 is driven by cytokine production, including interleukin (I.L.)-1β. This trial revealed that of the 52 patients who received anakinra and 44 patients who received standard of care, anakinra reduced the need for invasive mechanical ventilation and mortality in patients with severe COVID-19.
Anti-IL-6 receptor Monoclonal Antibodies
Interleukin-6 (IL-6) is a proinflammatory cytokine that is considered the key driver of the hyperinflammatory state associated with COVID-19. Targeting this cytokine with an IL-6 receptor inhibitor could slow down the process of inflammation based on case reports that showed favorable outcomes in patients with severe COVID-19. The FDA approved three different types of IL-6 receptor inhibitors for various rheumatological conditions (Tocilizumab, Sarilumab) and a rare disorder called Castleman’s syndrome (Siltuximab).
Need for a vaccine
The most fruitful way to prevent the spread of any disease would be to immunize the population towards the disease. This is where vaccines come into the picture. But to create a vaccine against a viral disease whose pathogen has the ability to mutate is quite tricky. Nonetheless multiple such efforts using various techniques have been successful and approved by the FDA for use. Let us take a look at them
BNT162b2 vaccine (Tonizameran)
This mRNA based vaccine has been developed by BioNTech/Pfizer. Individuals 16 years of age or older receiving two-dose regimen the vaccine when given 21 days apart conferred 95% protection against COVID-19 with a safety profile similar to other viral vaccines. Based on the results of this vaccine efficacy trial, the FDA issued a EUA on December 11, 2020, granting the use of the BNT162b2 vaccine to prevent COVID-19.
mRNA-1273 vaccine
This mRNA based vaccine has been developed by Moderna. Results from another multicenter, Phase 3, randomized, observer-blinded, placebo-controlled trial demonstrated that individuals who were randomized to receive two doses of the vaccine given 28 days apart showed 94.1% efficacy at preventing COVID-19 illness and no safety concerns were noted besides transient local and systemic reactions. Based on the results of this vaccine efficacy trial, the FDA issued a EUA on December 18, 2020, granting the use of the mRNA-1273 vaccine to prevent COVID-19.
Ad26.COV2.S vaccine (Johnson and Johnson vaccine)
It received EUA by the FDA on February 27, 2021, based on the results of an international multicenter, randomized,placebo-controlled multicenter, phase 3 trial showed that a single dose of Ad26.COV2.S vaccine conferred 73.1% efficacy in preventing COVID-19 in adult participants who were randomized to receive the vaccine.
ChAdOx1 nCoV-19 vaccine (Covishield)
It has a clinical efficacy of 70.4% against symptomatic COVID-19 after two doses and 64 % protection against COVID-19 after at least one standard dose. This too has been approved by multiple countries for use.
In addition to the vaccines mentioned above, as many as seven other vaccines, including protein-based and inactivated vaccines, have been developed indigenously in India(Covaxin), Russia(Sputnik V), and China(CoronaVac) and have been approved or granted emergency use authorization to prevent COVID-19 in many countries around the world.
References
Cascella M, Rajnik M, Aleem A, et al. Features, Evaluation, and Treatment of Coronavirus (COVID-19) [Updated 2022 Jan 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-
Copyright © 2021 Rodriguez-Guerra M, Jadhav P, Vittorio TJ. https://doi.org/10.7573/dic.2020-10-3. Published by Drugs in Context under Creative Commons License Deed CC BY NC ND 4.0.
Stasi, Cristina et al. “Treatment for COVID-19: An overview.” European journal of pharmacology vol. 889 (2020): 173644. doi:10.1016/j.ejphar.2020.173644
Wu K, Werner AP, Moliva JI, Koch M, Choi A, Stewart-Jones GBE, Bennett H, Boyoglu-Barnum S, Shi W, Graham BS, Carfi A, Corbett KS, Seder RA, Edwards DK. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. bioRxiv. 2021 Jan 25
( This article is second in the series of articles 'Pandemic at a perspective')