The COVID-19 (Coronavirus) infection has affected 2,128,751 patients throughout the world with 1,42,651 deaths until now (16/04/2020: 09:50 pm). Studies are going on to find an effective drug that could reduce the mortality and shorten the hospital stay. Most of the drugs that are used to treat COVID-19 infections throughout the world in the ICUs and wards are either antivirals or immune modulators. The plasma (convalescent sera) of individuals who have healed from COVID-19 infection is also administered to serious patients who require ventilatory assistance. However, except for Remdesivir, an antiviral drug that has been granted approval for use in severe COVID-19 patients on a compassionate basis, none of the other drugs have gained much popularity.
Antivirals, Immune-modulators, and Plasma?
Like most viral infections, it is not the virus that is causing cellular destruction. It is the host immune response that becomes wary and starts killing all the "flagged" cells that are hosting the virus. So, in essence, we need a combination of two drugs - a drug to kill the virus and a drug to control the host's excessive immune response. Thus, most logical therapies would include an antiviral drug like remdesivir, favipiravir, and others and an immune-modulator like antimalarial drugs, glucocorticoids, and Interleukin-6 inhibitors (Tocilizumab). Antiviral drugs halt the replication of the viral genome. Antimalarial drugs, zinc, other unapproved medicines are believed to act at cellular levels inhibiting the viral replication. Another logical approach would be to infuse antibodies that could bind the antigens. Intravenous immunoglobulins (IVIGs) are given or plasma from patients who have healed from COVID-19 infection is transfused in this way. Plasma and IVIGs directly bind to antigens and antibodies preventing cellular destruction caused by inflammatory cells. 
Here, I discuss some of the antiviral drugs that possess activity against the COVID-19 infection. Although antimalarials have got antiviral properties and are among the most popular drugs used to treat COVID-19 infection, they are not discussed here.
Antiviral Drugs for the Treatment of COVID-19 infection:
Several antiviral drugs have been tried until now in patients infected with COVID-19. Trials are on-going. The following discussion is a brief overview of these trials and updates.
Remdesivir:
Remdesivir is an investigational nucleotide analog antiviral drug that has got antiviral activity against viruses in the Coronavirus family
The Spectrum of activity of Remdesivir:
A broad-spectrum antiviral medication called Remdesivir has potency in opposition to the following viruses:
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- MERS-CoV
- Respiratory syncytial virus
- Nipah virus
- Ebola virus
- Marburg
- Hendra virus
- SARS-CoV
Remdesivir's mode of action:
As a result, viral RNA transcription is prematurely stopped.
Remdesivir Clinical Studies:
Remdesivir was primarily investigated to treat Ebola. Remdesivir has been used in SARS-CoV as well as MERS-CoV investigations as a preventative and therapeutic treatment, and improvements in respiratory functioning, weight loss, and viral replication were seen. It was found to be more useful than Lopinavir/ ritonavir and Interferon-Beta combined [Ref].
Remdesivir studies in COVID-19 infection:
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- Gilead Pharmaceuticals, the product's maker, is currently researching it. Two phase 3 clinical investigations are ongoing at the moment.
The first research will assess Remdesivir's effectiveness and safety in treating people with severe COVID-19 virus. The effectiveness and safety of the medication are assessed in the second study in patients with mild to moderate COVID-19 infection.
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- Two studies have been initiated by the China health authorities. These analyses will assess the safety and effectiveness of Remdesivir in patients who have severe disease and require hospitalization and Oxygen support. The second study will only include hospitalized patients who are stable enough and do not require oxygen.
- Using standards established by the WHO, the National Institute of Allergy and Infectious Diseases (NIAID) in the United States and INSERM in France have started placebo-controlled studies in adults testing Remdesivir.
- All these studies are being provided by Gilead free of cost [Ref].
Remdesivir for Patients with Severe COVID-19 Infection: Compassionate Use [Ref]:
This study included 61 patients with COVID-19 infection who also were receiving oxygen support or breathing room air with an oxygen saturation of 94 percent or below.
Remdesivir was given to patients at doses of 200 mg on day 1 and 100 mg every day for nine days (Total 10 days).
68% of the patients in the study had an improvement in oxygen, including 57% of the patients requiring mechanical ventilation were extubated.
Dose of Remdesivir in COVID-19 infection:
<40 kg: On day 1, a single intravenous dose of 5 mg/kg/dose is given, then 2.5 mg/kg/dose is given once day.
≥40 kgs and adults: On day 1, a single intravenous dose of 200 mg was given, and thereafter 100 mg was given once daily.
Time: 5 - 10 days
Side effects of Remdesivir:
Data is very limited in this regard. Here are a few of the negative effects that have been documented in studies: [Ref]:
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- Hypersensitivity reactions
- Phlebitis at the infusion site
- Constipation
- Headache
- Ecchymosis
- Nausea
- Pain in the extremity
- Transaminitis
- Renal dysfunction
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Lopinavir/ Ritonavir: (Ref)
The spectrum of antiviral activity:
It is a protease inhibitor. It has activity against HIV infection and is primarily approved for this purpose. It has also been found in studies to be effective against SARS infection [Ref] and is presently being studied for the therapy of COVID-19 infection.
Mechanism of action of Lopinavir/ Ritonavir:
The protease inhibitor lopinavir prevents the viral Gag-Pol polyprotein precursors from being broken down into individual proteins. As lopinavir inhibits the enzyme CYP3A, ritonavir is used in conjunction with it to raise its plasma levels.
Clinical studies of Lopinavir and Ritonavir:
Researchers took interest in this drug combination when two case reports reported clinical improvement and reduction in the viral load with the drug in COVID-19 infected patients [Ref].
Also, it was previously studied in SARS infection which is also a coronavirus. Another study published in the NEJM recently titled "A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe COVID-19" did not find it effective.
In the research, there was no evidence of a significant reduction in mortality or clinical improvement with lopinavir/ritonavir. It did not lessen the amount of viral RNA present or the time it remained detectable.
However, patients in the lopinavir group had a fewer number of patients who develop serious complications such as secondary infections and renal failure. Besides, fewer patients in the lopinavir group required mechanical ventilation or non-invasive ventilation.
The dose of lopinavir/ ritonavir in COVID-19 infection:
During a 14-day treatment period, 400/100 mg of lopinavir/ritonavir are given twice daily.
Details of the dosing are discussed here - Kaletra (Lopinavir and ritonavir)
Side effects of Lopinavir/ Ritonavir:
Most patients develop gastrointestinal symptoms such as nausea, diarrhea, and dyspepsia. Other common side effects include cytopenias, hypertriglyceridemia, and hepatic dysfunction.
Details of the side effects are discussed here - Kaletra (Lopinavir and ritonavir)
Favipiravir:
Favipiravir is an antiviral drug that was accidentally discovered at the Research Laboratories of Toyama Chemical Co., Ltd. It was primarily intended for the treatment of viral influenza.
The spectrum of activity of Favipiravir:
It is quite effective against a variety of viral infections. These viruses come from the Bunyaviridae, Filoviridae, Rhabdoviridae, Paramyxoviridae, Flaviviridae, Togaviridae, Picornaviridae, and Caliciviridae families, among others.
Details of the antiviral activity are discussed here: Favipiravir (Avigan) for the Therapy of COVID-19 infection.
Mechanism of action of Favipiravir:
It inhibits the viral RNA polymerase.
Clinical studies of Favipiravir in COVID-19 infections:
One study compared Favipiravir with Arbidol in the therapy of COVID-19 condition [Ref]. Arbidol is a Russian-made potent broad-spectrum antiviral drug that is available in China and Russia. It is primarily used to treat patients with influenza.
The study did not demonstrate the effectiveness of Favipiravir as determined by clinical recovery on day 7. However, symptoms of fever and cough improved earlier in the Favipiravir group compared to Arbidol.
The Dose of Favipiravir:
The dose in COVID-19 infection is not yet very clear. However, it has been used in doses of 30 mg/kg/day in two to four divided doses.
It was administered twice daily in doses of 800 mg for the first two to five days in order to treat influenza. The initial dose was 1800 mg twice daily.
It was given in dosages of 2400 mg, 2400 mg, and 1200 mg every eight hours on day one for treating Ebola virus infection, as well as a maintenance dose of 1200 mg twice day. [Ref].
Side effects of Favipiravir:
Side effects are minimal at the recommended doses. These include gastrointestinal side effects like nausea, altered taste, and flatulence. Other side effects include hepatic dysfunction and hyperuricemia.
It can also cause QT prolongation [Ref] and is embryotoxic.
Oseltamivir:
Oseltamivir is an antiviral medication that has been authorised for both the prevention and treatment of both seasonal and avian influenza.
The spectrum of activity of Oseltamivir (Tamiflu):
Oseltamivir is authorised for the prophylaxis and treatment of avian influenza, including H7N9, H5N1, and H9N2, as well as the prophylaxis and treatment of seasonal influenza A and B infections.
Mechanism of action of Oseltamivir:
It inhibits viral replication by inhibiting the viral Neuraminidase that cleaves the budding viral progeny from its attachment point to the cellular envelope before its release.
Clinical studies of Oseltamivir in COVID-19 infections:
Oseltamivir has been found to possess some effectiveness against COVID-19 infection. One case report found significant radiological clearance after 3-days treatment with oseltamivir [Ref].
Doctors used Oseltamivir in the majority of the COVID-19 infected patients during the initial outbreak in Wuhan, however, no powerful conclusion could be drawn from the effects of the treated individuals.
The Dose of Oseltamivir:
It is given twice daily for five days at a dose of 75 mg to treat influenza infection.
It is given twice daily for five days at a dose of 150 mg to treat COVID-19 infection.
The Side effects of Oseltamivir:
Common side effects of Oseltamivir include headache, nausea, vomiting, and dyspepsia. It can also cause serious neuropsychiatric symptoms such as delirium, confusion, hallucinations, and self-injury.
Details of the side effects of Oseltamivir and contraindications are discussed here: Tamiflu (Oseltamivir) - Uses & Doses (including Dosage in COVID-19)
In Conclusion:
Antiviral drugs that have demonstrated some efficacy against COVID-19 infection include Remdesivir, Lopinavir/Ritonavir, Favipiravir, and Oseltamivir. Trials are being conducted to evaluate the safety and efficacy of these drugs. Let's hope!
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