MEDICINES FOR COVID TREATMENT
For Information and Understanding of COVID-19 read:
Introduction and Evolution
The majority of COVID patients require only symptomatic treatment. During the initial part of the pandemic, some drugs which were specifically developed and approved in the past for other infections were researched and tried as medicines for COVID treatment in certain patients and are therefore called repurposed medicines for COVID. More studies and research are required and ongoing to confirm the effectiveness of many of the drugs mentioned below, for various parameters of COVID treatment. Later medicines were developed specifically for COVID. All these drugs are mainly indicated for moderate-severe or high-risk cases and are not needed in the majority of people with mild COVID treated in home isolation.
All these drugs can have side effects that need to be clinically monitored, especially when given in combination, and to patients with pre-existing medical conditions. Therefore these medicines should be used appropriately as part of COVID treatment, depending on patient type, disease severity, and presence of associated co-morbidities. Most importantly, none of these drugs should ever be taken without the prescription and monitoring of a qualified physician. Also, none of these drugs have any evidence from studies on efficacy against the new Omicron variant.
These drugs act by preventing the replication of the virus inside host cells. They are of use only in the first few days of the disease and symptoms, and in only certain limited cases.
This drug (originally developed for the Ebola virus) given by intravenous injection (infusion) has been approved for treating all hospitalized COVID patients. It targets the enzyme RdRp (RNA dependent RNA polymerase) required for viral replication.
The large SOLIDARITY trial by WHO showed no significant effect of remdesivir on reducing overall mortality, initiation of ventilation, and duration of stay in hospitalized patients. However, the smaller ACTT1 trial showed an overall reduction in recovery time and mortality in the subgroup of patients on oxygen therapy. It is approved by the USFDA, EU, and DCGI-India.
Remdesivir is mainly useful for patients hospitalized for breathlessness, lowered oxygen saturation levels needing oxygen therapy, and severe lung involvement and pneumonia. It should be initiated within the first few days of the symptoms (maximum within 10 days) and often is not of much use in patients who are usually hospitalized in the second week (inflammatory phase) of the disease.
A recent study (PINETREE) has shown that a 3-day course of remdesivir given in the first week of disease in an outpatient infusion facility or at home OPD/home injection can result in an 87% lower risk of hospitalization or death in high-risk patients with comorbidities.
This drug (originally an anti-flu drug) is given orally and has been approved in some countries like India, and the EU for mild-moderate COVID patients, especially those in home care or health centers. It also targets the RdRp enzyme.
In clinical studies, favipiravir has shown a shortening of recovery time and faster symptomatic relief, along with more rapid viral clearance and reduced shedding. It is still not convincingly established if favipiravir changes the clinical course, and whether it helps decrease hospitalization risk or complications, need for oxygen therapy, or transmission in the family and community. It is of use when given within 5 days of symptom onset, and not required in most cases.
This is another recent antiviral drug developed and it acts by inhibiting the replication of certain RNA viruses like SARS-CoV-2 by promoting widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase enzyme.
Molnupiravir has shown in clinical studies to reduce hospitalization rates by around 30% in COVID-positive patients when given within 3-5 days of symptom onset. It has been approved by USFDA in Dec 2021 for mild-to-moderate COVID in those aged 18 years or more, who are unvaccinated or at high risk for progression to severe COVID, including hospitalization or death, and for whom alternative approved COVID treatment options are not accessible or clinically appropriate.
It has also been given emergency use approval by the European Medicines Agency (EMA) and the Drug Controller General of India (DCGI). However, there is concern over possible adverse effects which are being monitored closely by all regulatory agencies.
Paxlovid (nirmatrelvir-PF-07321332 with ritonavir)
This drug has been recently developed and is the first oral antiviral for COVID authorized by USFDA in Dec 2021. It acts by binding to and inhibiting the SARS-CoV-2 virus’ main protease enzyme (Mpro), thereby preventing viral multiplication.
Paxlovid has shown in clinical studies to reduce hospitalization rates significantly by almost 90% in COVID-positive patients when given within 3-5 days of symptom onset.
Paxlovid has been approved by USFDA for mild-to-moderate COVID in those aged 12 years or more who are at high risk for progression to severe COVID, including hospitalization or death. It is positioned especially for unvaccinated people and/or those with risk factors or comorbidities. It has also been authorized by the European Medicines Agency (EMA).
Drugs like lopinavir-ritonavir had been tried initially with some success in certain countries where the above drugs were not yet available. They may be useful in patients in whom lymphocyte count is extremely low. However, this combination has not shown benefit in hospitalized COVID patients according to the WHO SOLIDARITY drug trial.
Other anti-HIV drugs like zidovudine are still under evaluation for COVID and studies are awaited. As of now, anti-HIV drugs are not part of COVID treatment recommendations.
This is a drug, developed and approved in India during the 2nd wave in Apr-May 2021 post a small phase 3 clinical trial showing a reduction in oxygen requirement or dependence, and a faster recovery time. This drug is in a powder sachet form to be taken orally after dissolving in water.
It acts by specifically accumulating in the virus-infected cells, preventing viral growth and energy production, and maybe a useful adjunct in moderate-severe COVID patients hospitalized for low oxygen saturation. However, more data is needed from larger and randomized control studies.
Nitric Oxide Nasal Spray (NONS)
NONS has been recently launched in some countries like India. This nasal spray has shown efficacy in significantly reducing viral loads and COVID severity in phase 2 and 3 trials. It acts by creating a physiochemical barrier in the nose and upper airways by its viricidal (virus killing) effects.
Other nasal and oral sprays are being developed that contain active ingredients and excipients derived from food products that mimic the action of soap (fatty acids with detergent action). These are capable of disintegrating enveloped viruses and pathogens like influenza and coronaviruses and their variants. Research and clinical data are awaited.
These are signaling antiviral proteins part of our immune system. PEG Interferon alpha-2b injection has recently been approved in countries like India for treating moderate COVID to reduce viral load and improve recovery.
Some preliminary evidence has come in about Interferon-beta treatment in an inhalational form to prevent severe disease and lung damage in COVID patients, but still conclusive studies are awaited.
This was being prescribed (sometimes along with the antibiotic doxycycline), in mild-moderate non-hospitalized COVID cases. Ivermectin is known to have antiviral properties and in some clinical studies initially, it has shown shorter recovery time, along with better symptomatic relief and clinical course.
Ivermectin also showed effectiveness as a prophylaxis drug for people with documented exposure to COVID in one study. Data from large clinical trials have not confirmed the definite place of ivermectin in managing COVID. However, ivermectin is very economical and was part of treatment protocols advocated by medical associations in some countries like India during the 2020-21 waves, but not subsequently.
Another anti-parasitic drug nitazoxanide is also being studied but no conclusive data has emerged yet.
This is an oral anti-malaria, and anti-rheumatoid arthritis (RA) drug was being used in some countries. It has been studied individually and also with the antibiotic azithromycin. Results were initially encouraging in some clinical studies which showed a reduction in viral shedding, hospitalization rate, ICU admission, and mortality when given early in the course of mild-moderate non-hospitalized COVID patients. However other subsequent clinical studies have refuted the same. Hydroxychloroquine has not shown benefit in severe cases or hospitalized patients according to the WHO SOLIDARITY and other recent trials.
Caution and monitoring with ECG (for QT interval prolongation or heart rhythm abnormalities) are advised, especially in elderly COVID patients with other co-morbid health conditions, and if given with antibiotics like azithromycin. Hydroxychloroquine is still part of COVID treatment regimens in mild non-hospitalized cases, in some countries due to it being economical.
Hydroxychloroquine has also been approved in a few countries like India to prevent symptomatic or severe COVID in exposed or infected health care workers and close/household contacts, however definite supportive scientific evidence is lacking for this.
Antibiotics are not routinely recommended in COVID patients unless there is reason to suggest that a secondary bacterial infection is present, causing sore throat, pain on swallowing, and cough.
Azithromycin is sometimes prescribed in such cases but should not be used indiscriminately used. There is no proven role or clinical recommendation for using doxycycline.
Antibiotics are sometimes also given to hospitalized patients to prevent bacterial infections when on immune-suppressive drugs.
These include dexamethasone, prednisolone or methylprednisolone (oral/injectable). Corticosteroids have shown effectiveness in clinical studies in reducing inflammatory lung damage and mortality in moderate-severe hospitalized COVID patients especially those on ventilators or requiring oxygen therapy.
So far, only corticosteroids have been proven effective for severe or critical hospitalized COVID-19 patients. Corticosteroids should not be given in mild non-hospitalized COVID patients in the first week of illness especially if their oxygen saturation is adequately maintained and their inflammatory markers are normal. They may be introduced in the second week in case fever or cough is persistent or comes back, inflammatory markers like CRP are significantly raised or rising, and oxygen saturation is showing a tendency to fall below 94%. In such cases, they are given orally as low dose tablets, or more preferably as inhalers (budesonide).
Giving steroids to recovering patients with mild symptoms and maintained oxygen saturation can do more harm than good, therefore the appropriate usage and timing of these medicines is crucial. Prolonged and high-dose steroids are associated with suppression of immunity, rise in blood sugar, and risk of Mucormycosis.
This is an oral anti-arthritic drug is also sometimes used as an anti-inflammatory agent (usually along with remdesivir) for hospital-based COVID treatment especially in those people non-responsive to or who can’t be given corticosteroids or have very low lymphocyte count.
Recently this drug has been recognized by WHO for treating COVID patients as add on to steroids and as an oral and safer alternative before starting tocilizumab or itolizumab.
Tocilizumab is injectable anti-RA drug (anti-IL-6 cytokine), is indicated in hospitalized patients for reducing severe lung damage and symptoms caused by a ‘cytokine storm’ (a damaging hyper-immune reaction with massive inflammation, and rapidly rising inflammatory markers).
Sarilumab, another anti-RA anti-IL-6 drug is also available for this indication. Patients admitted to ICU and not showing improvement in the next 24-48 hours despite corticosteroids and high flow nasal oxygen, may be suitable candidates for such drugs.
Itolizumab, an injectable anti-psoriasis drug, has also been approved for limited emergency use in such COVID cases.
Due to the shortage of these drugs, some hospitals are also using other substitutes like bevacizumab, etc. but both regulatory approval or clinical evidence is absent. Any active infection should be ruled out before using these drugs, and being strong immunosuppressants there should be close monitoring for adverse effects.
Cytokine absorption filters (cytosorb) are available as kits for hospital use during cytokine storms. This helps remove inflammatory mediators from the pumped-out patient’s blood after which the blood is recirculated back to the patient.
This is an injectable anti-inflammatory (protease inhibitor) drug used for sepsis and pancreatitis, that reduces inflammatory markers and cytokines. It may be used, often with corticosteroids in hospitalized COVID patients with progressing lung damage, ARDS, or during a cytokine storm, to decrease complications, need for mechanical ventilation and risk of mortality.
This is given through a nebulizer, as sublingual tablet or injection. It has also shown some anecdotal benefit in temporarily improving oxygen saturation and reducing inflammatory markers involved in a cytokine storm, but large-scale studies are still needed to verify its use, place in treatment, and benefit.
It is an oral anti-inflammatory anti-RA drug, has shown some evidence of reducing mortality, hospitalization, and the need for ventilation when given early after COVID diagnosis in non-hospitalized RT-PCR positive patients. (recent COLCORONA study).
It may be a useful option instead of corticosteroids in mild-moderate home care COVID patients who have additional risk factors like diabetes, high BP, heart disease, obesity, or known respiratory disease especially if they have high fever (>101 def F) and low lymphocyte counts. However, more research is still needed to ascertain a definitive role. Colchicine has not shown benefit in hospitalized COVID patients.
Vitamin C is a known anti-oxidant showed some limited case-based and anecdotal evidence of suppressing massive inflammation in the body especially during a ‘cytokine storm’ in some hospitalized COVID patients, when given as injections in very high doses.
Aspirin (used early in low dose in mild-moderate cases) can have protective effects on the endothelium by its anti-inflammatory and anti-platelet (anti-thrombotic) action. Aspirin should be continued in patients already taking it for cardiovascular disease and its risk factors.
Low molecular weight Heparins (LMWH) are anticoagulant drugs like enoxaparin, injected subcutaneously and used in hospitalized patients with an increased risk of thrombosis.
Directly acting oral anticoagulants like apixaban and rivaroxaban are used in those discharged from the hospital or rarely in non-hospitalized patients with high D-dimer suggesting thrombosis risk.
Anticoagulants should not be used routinely or indiscriminately in non-hospitalized or mild-moderate homecare patients. Another investigational drug, nafamostat, also an anticoagulant, is under clinical trial for its anti-viral properties of inhibiting entry and activation of SARS-CoV-2 in human cells.
Statin group of cholesterol-lowering drugs (like atorvastatin) also have anti-inflammatory and antithrombotic properties that help protect blood vessels and thereby reduce endothelial damage and dysfunction. As of now, these drugs should be continued in patients already on them for cholesterol control and cardiovascular disease. These drugs are being further evaluated for their likely benefits as an adjunct therapy in COVID patients.
In November 2020, biological monoclonal antibody drugs casirivimab-imdevimab and bamlanivimab-etesevimab (as combinations) and in May 2021, another one sotrovimab have been approved by the US FDA for treating mild-moderate COVID patients 12 years or older at high risk for progressing to severe COVID, complications, and hospitalization. This includes those who are 65 years of age or older, or who have certain associated comorbid medical conditions like diabetes, hypertension, heart disease, kidney disease, respiratory conditions, obesity (BMI of 35 or more), and immunosuppressive diseases/therapy.
These agents are given together as a single intravenous infusion and act specifically against the spike protein of the coronavirus to prevent its entry into human cells. These agents work best if given within 72 hours of symptom onset (maximum within a week). They are not to be used in already hospitalized patients and those requiring oxygen therapy or ventilation.
Out of these sotrovimab has some activity against Omicron, but this is still under further study and research, and is not yet available in India.
Convalescent Plasma is the non-cellular component of the blood from recovered patients which contains antibodies to the COVID virus. It is being used to treat certain severe and non-responsive hospitalized cases and has helped in the recovery of some patients. However, clinical studies currently have not been able to confirm its efficacy or benefits, and more research is needed before it can be recommended.
Plasma therapy mainly has value if antibody titers are high, and it is given early in the disease course. Its large-scale feasibility and effectiveness are still inconclusive.
IVIg (Intravenous Immunoglobulin)
It is also used in severe patients non-responsive to other drugs and therapies, in some COVID hospitals. Though some studies have shown improvement in clinical outcomes and reduction in mortality, more data is needed on the timing and group of patients who would actually benefit. It may be useful to manage post-COVID multisystem inflammatory syndrome (MIS).
Preformed concentrated COVID antibodies (hyper-immune globulin) have also been developed for treatment and short-term prophylaxis, but more large-scale data is still awaited on the use of these therapies.