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BRIEF COMMUNICATION
Year : 2022  |  Volume : 4  |  Issue : 1  |  Page : 15

Remdesivir Use and Controversies in COVID-19 Pneumonia: Myths and Reality!


1 Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra, India
2 Department of Pharmacology, MIMSR Medical College, Latur, Maharashtra, India
3 Department of Internal Medicine, MIMSR Medical College, Latur, Maharashtra, India

Date of Submission28-Mar-2022
Date of Acceptance26-Jul-2022
Date of Web Publication30-Aug-2022

Correspondence Address:
Dr. Shital Patil
Department of Pulmonary Medicine, MIMSR Medical College, Latur, Maharashtra 413 512
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JTCCM-D-22-00010

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How to cite this article:
Patil S, Mugalikar A, Patil D, Gondhali G. Remdesivir Use and Controversies in COVID-19 Pneumonia: Myths and Reality!. J Transl Crit Care Med 2022;4:15

How to cite this URL:
Patil S, Mugalikar A, Patil D, Gondhali G. Remdesivir Use and Controversies in COVID-19 Pneumonia: Myths and Reality!. J Transl Crit Care Med [serial online] 2022 [cited 2022 Dec 3];4:15. Available from: http://www.tccmjournal.com/text.asp?2022/4/1/15/355054




  Remdesivir and its Use in COVID Pneumonia: “Available Evidence” Top


Remdesivir is a nucleotide prodrug of an adenosine analog. It binds to the viral RNA-dependent RNA polymerase and inhibits viral replication by terminating RNA transcription prematurely. Remdesivir has demonstrated in vitro activity against syndrome coronavirus 2 (SARS-CoV-2). In a rhesus macaque model of SARS-CoV-2 infection, remdesivir treatment was initiated soon after inoculation; the remdesivir-treated animals had lower virus levels in the lungs and less lung damage than the control animals.[1]

Remdesivir has been approved on May 1, 2020, by Food and Drug Administration (FDA) for its emergency use in coronavirus disease-2019 (COVID-19) in adults and children above 12 years of age exclusively in indoor care facilities. In India, the Central Drugs Standard Control Organization approved its use for the treatment of severe COVID-19 patients on June 20, 2020.[2] The FDA on August 28, 2020, broadened the therapeutic applications of the drug to include hospitalized patients regardless of disease severity. On October 16, 2020, the Indian Council of Medical Research (ICMR) issued a press release stating that the interim analysis of SOLIDARITY trial revealed that no benefits were observed in Remdesivir-treated COVID-19 patients (or any other drug tested in the study)-treated COVID-19 in any group (asymptomatic/mild/moderate/severe/critical) of patients. Exactly a week later, the US FDA approved Gilead's New Drug Application for the use of remdesivir in adults and pediatric patients for the treatment of COVID-19 which necessitates hospitalization. This FDA approval changed the status of remdesivir from emergency use approval to full approval.[3]

As per the Ministry of Health and Family Welfare (MOHFW) and ICMR India on April 23, 2021, Remdesivir should be used only in select moderate/severe hospitalized COVID-19 patients on supplemental oxygen as it is a reserve drug approved under Emergency Use Authorization only based on limited scientific evidence globally and should not use in mild COVID-19 patients who are in home care/COVID Care Centers.[4]

Remdesivir use in COVID-19 has been evolved over the last 1 year and research data from trails is available suggesting its use and also of no benefit; clinching overall clinicians' decision to use in indoor setting. “Adaptive COVID-19 Treatment (GM1) Trial” found that Remdesivir is useful in cases of COVID-19 with SpO2 < 94% on room air (moderate-to-severe cases) if it is administered within 7–10 days of illness. Remdesivir led to a shorter median time from randomization to recovery (10 days, vs. 15 days with placebo) and may have reduced the time to hospital discharge (12 days vs. 17 days) but did not show a mortality benefit.[5] The “Solidarity Trial” conducted by the WHO in 30 countries from March 2020 at 405 hospitals; 11,330 adults underwent randomization; 2750 were assigned to receive Remdesivir. The interim results of the “WHO Solidarity trial” published in December 2020 showed that Remdesivir had little or no effect on hospitalized patients with COVID-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay.[6]


  Remdesivir's Role in Changing Strains of CoronaVirus in Coronavirus Disease-2019 Pandemic Top


Although mortality documented in COVID-19 is less as compared to SARS and MERS, various variants evolved during COVID-19 disease have different trends of mortality. Importantly why the second wave “delta” variant of COVID-19 has highest mortality as compared to first wave variant, and negligible in third wave omicron variant, is still unknown. Maybe, genetic makeup of coronavirus was the determining factor for overall outcome in the first and second wave different variants of coronavirus with genetic mutations; which was associated with increased morbidity and mortality in comparison to currently ongoing omicron variant with negligible mortality.

In the second wave COVID-19, many patients were affected with “Delta variant” of coronavirus mutant-related disease, were presented in advanced stage and majority of cases required intensive care unit hospitalization, oxygen and ventilatory support requirement, Remdesivir use in the maximum number of cases during hospitalization. In comparison to the first wave with maximum COVID-19 cases were mild with few cases requiring intensive care facility; proportionately maximum cases in the second wave required all facilities in critical care setting. Although health system has more prepared for intensive care facility during the second wave, due to rapidly growing pandemic and rapid pouring large number of moderate-to-severe-to-critical COVID-19 cases has created shortage of all supportive measures required in management of these cases in the intensive care setting such as ventilators, oxygen supply and Remdesivir and created demand supply inadequacy. During the same time, due to rapidly evolving-worsening nature of COVID-19 pneumonia in a greater number of cases, demand of Remdesivir was increased, as it was used in mild cases also and created shortage availability. To tackle shortage of Remdesivir and more panic created by social media regarding its scarcity and chances of its use in mild cases, MOHFW and ICMR India, formulated guidelines and advised Physicians/Doctors regarding judicious use in COVID-19 cases and extreme caution to be taken while using this reserve/experimental/emergency use authorization drug Remdesivir to stop its misuse as this is only an experimental drug with potential to harm, has relatively high cost and has limited availability.[4] Remdesivir was used in both the waves and documented benefit in terms of decrease in overall duration of hospitalization, while very negligible effect on mortality benefit in both the waves, and whatever mortality benefit was documented especially in the second wave as compared to the first wave. Rationale for the relative benefit of Remdesivir in the second wave was that it was used in the early stage of illness with steroids as many cases were present in rapidly evolving pneumonia.


  Remdesivir Use-Related Myths and Reality in Coronavirus Disease-2019 Pneumonia Top


Overview

COVID-19 pneumonia is a heterogeneous disease with variable effect on lung parenchyma, airways, and vasculature leading to long-term effects on lung functions. Although the lung is the primary target organ involvement in COVID-19, many patients were shown pulmonary and extrapulmonary manifestations of diseases variably during the first and second waves, which occurred as resultant pathophysiological effects of immune activation pathway and direct virus-induced lung damage. In recovered COVID-19 pneumonia cases, proportionately, a large number of affected patients were having “long COVID” manifestations documenting some systemic symptoms even after 18 months of discharge from the critical care setting. Many cases are lingering with long COVID manifestations ranging from minor to major illnesses affecting quality of life, and its impact on morbidity and mortality later during course of illness over a period of time.

Social media has played a crucial role in spreading wrong message regarding doubtful role of Remdesivir in COVID-19 and these nonscientific comments and statements spread without available research has created misunderstanding in majority of recovered cases, especially in those facing “long COVID” manifestations. In an Indian study[7] it was observed, 8% patients had an ongoing symptomatic phase of COVID, lasting 1–3 months, and 31.8% patients had post-COVID phase, with symptoms lasting 3–12 months. Eleven percent patients continued to have at least one symptom even at the time of the second interview (9–12 months from the disease onset). Long-COVID was reported in almost 40% of this study group. The occurrence of post-COVID symptoms had no correlation to age, gender, comorbidities or to the disease severity. The duration of symptom resolution was also not associated with age, gender or comorbidity but was found to be significantly associated with severity of illness at the time of admission. Fatigue was significantly more prevalent amongst the elderly patients and in those who had severe COVID-19. Persistence of breathlessness was significantly more often reported by those patients, who had severe illness at presentation. The presence of neuropsychiatric symptoms such as depression, anxiety, “brain fog” and sleep disorders was reported in nearly 9% of cases. No patient reported any significant organ damage. A significant number of patients (16.5%) continued to have some form of post-COVID symptoms for as long as 6–12 months, a majority of them, had resumed their routine work much earlier. 31.2% patients took 1 month to resume daily routine while 6.4% took almost 4 months to resume their daily routine (study represents data from follow-up of sick patients who are likely to have more chances of post-COVID symptoms).

Renal dysfunction

Most common myth, what we have observed is fear of renal dysfunction after Remdesivir use in COVID-19 cases. Rational for fear is that incomplete knowledge shared by social media and second is that majority of recovered cases were having either one systemic long COVID symptom. Real fact is that, patients with chronic kidney disease (CKD), especially those with end-stage renal disease, are susceptible to the development of severe COVID-19, which is associated with high mortality. Apart from respiratory support depending upon the severity of the respiratory involvement, management of COVID-19 is largely supportive. The active metabolite of remdesivir is eliminated by the kidneys and can accumulate in patients with reduced estimated glomerular filtration rate (eGFR); moreover, the sulfobutylether-β-cyclodextrin (SBECD) carrier is known to accumulate in these patients. SBECD was designed to address this problem; it remains in an ionized state after glomerular filtration and does not undergo significant tubular reabsorption. Although SBECD accumulates in patients with decreased eGFR, elevation in the serum creatinine did not correlate with SBECD levels. Moreover, the SBECD carrier is effectively removed by dialysis; a 4-h session removes almost half of the accumulated SBECD. Study in India[8] documented that remdesivir was well tolerated in patients with acute kidney injury (AKI) and CKD including those on hemodialysis, other studies[9] documented that patients without underlying liver disease who are expected to undergo continuous or intermittent dialysis or those with AKI expected to be transient may be the best initial candidates to receive remdesivir. The largest clinical trial[5] evaluating the use of this agent in COVID-19 excluded patients with stage 4 CKD or those requiring dialysis (i.e., eGFR < 30 mL/min/1.73 m2) and show that Remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection. We have documented enough scientific data regarding safety of Remdesivir in established kidney disease patients, and there is negligible chance of renal dysfunction after its use in COVID-19 pneumonia cases.

Mucormycosis

We have also documented, fear of Mucormycosis or “black fungus” after Remdesivir use in COVID-19 cases. Mucormycosis, both pulmonary and extrapulmonary (eyes, nose, sinuses, cerebral), a fungal infection as a complication documented during evolution of COVID-19 lung pneumonia predominantly in second wave as compared to first wave across the country. Rational for documentation especially in second wave was unclear, may be related to more steroid use due to rapidly evolving acute respiratory distress syndrome and more virulent nature of Delta variant, corona virus-mucor fungus symbiosis to gain access through mucosal inflammation in airways, humidifier chamber of oxygen supplementation system contamination with fungal spores, but exact reason was unknown. Occurrence of Mucormycosis was never documented before with any respiratory virus-related pandemic as caused with influenza virus as in Spanish flu or corona virus related epidemics like SARS or MERS. Authors in their study[10] mentioned 3 possible theories for COVID-19 Associated Mucormycosis related to immune and inflammatory processes: (1) COVID-19 causes significant lymphopenia, resulting in a dramatic reduction in the availability of T cells (CD4+ and CD8+) and opening the entry gate for opportunistic fungal infections; (2) Increased pro-inflammatory markers in patients with severe disease; and (3) Pronounced damage of pulmonary tissues by COVID-19 aids the invasive fungi, especially the airborne ones or those that attack through the respiratory system. Hyperferritinemia caused by excess interleukin-6 release and macrophage activation results in increased availability of free iron within cells. This, in turn, causes endothelial destruction and inflammation called endothelitis. Thus, COVID-19——induced immunosuppression increases the risk of opportunistic infection, damages the endothelium and alveoles, easing the port of fungal invasion, and increases the glucose level due to the acute diabetes-like state caused by pancreatic damage; increased ferritin level supports fungal growth, and increased body temperature is optimal for thermotolerant fungi.[10] The ICMR released guidelines[11] for the screening, diagnosis, and management of mucormycosis in patients with COVID-19. The most common causes attributed to the rise of mucormycosis in COVID-19 patients are uncontrolled diabetes, the excessive use of corticosteroids for immunosuppression, and long-term stays in the intensive care unit. Even though no official figures about mucormycosis in COVID-19 cases were released by the Union Health Ministry during the first wave of COVID-19, India contributed to approximately 71% of the global cases of mucormycosis in patients with COVID-19 based on published literature from December, 2019, to the start of April, 2021.[12] Thus there is no any scientific evidence regarding association of Remdesivir and mucormycosis, thus this is a true myth.

Neurological symptoms

Another important myth documented after Remdesivir use as neurological symptoms ranging from anxiety, depression, impaired memory, shortened attention span or inadequate concentration labeled ad “Brain fog,” posttraumatic stress disorder more often in post-COVID care setting. In one study[13] authors documented that study COVID-19 tends to produce a wide range of symptoms, ranging from headache to anosmia to increased risk of stroke, that complicates clinical management. Potential neurologic effects and drug interactions have been reported secondary to the medications used to treat COVID-19. At this point in time, the exact mechanism involved in the neurologic manifestations of COVID-19 is not clear. However, in light of the aforementioned facts, COVID-19 could potentially have a long-term effect on the brain and may lead to impaired cognitive function, compromising the quality of life. Furthermore, lopinavir/ritonavir and azithromycin are used in the management of COVID-19. Their interaction with many common medications including antihypertensives, antiplatelets, statins, and anticoagulants has been reported in patients with prior strokes. Lastly, these medications also pose a risk of neurocognitive impairment when used for longer periods.[14] Future research defining whether SARS-CoV-2 exhibits neurotropism and/or initiates peripheral immune activation and hypercoagulation to affect brain function will be paramount for the development of efficacious therapies to mitigate the deleterious neurological consequences of COVID-19, including potential benefits in the management of acute respiratory failure. Thus, conclusive evidence of Remdesivir causing neurological adverse events including “Brain fog” is not available, and at present this is a complete myth.

Cardiovascular system

One more myth has been commonly observed in post COVID care setting, heart issues like ischemic heart disease, heart failure and long-term cardiac dysfunction after Remdesivir use in treatment of these cases in acute care setting. Available data[15] suggest that some patients with COVID-19 infection on Remdesivir may develop sinus bradycardia, hypotension, T-wave abnormalities, AF and a prolonged QT interval. Furthermore, few cases of cardiac arrest and complete heart block following Remdesivir infusion have been reported. It seems remdesivir have some cardiotoxic and proarrhythmic effects that are especially more pronounced in patients with previous cardiovascular diseases. Continuous cardiac rhythm monitoring is recommended in patients undergoing remdesivir treatment. It is especially advisable in individuals with any known cardiac diseases or electrolyte disturbances. Furthermore, we should be more cautious about additive cardiovascular adverse effects when other drug classes are used in addition to remdesivir treatment. This concludes that heart rate and rhythm monitoring is must while using Remdesivir during treatment of COVID-19 pneumonia cases and utmost precautions should be taken while using this drug in cases with underlying cardiovascular disease. We have documented safety of Remdesivir in the majority of cases with strict heart rate monitoring and avoided use in the setting of bradycardia or underlying rhythm abnormalities. We have also documented that bradycardia during treatment with or without Remdesivir in the intensive care unit is actually a clinical marker of satisfactory treatment outcome. Thus, Remdesivir may be associated with adverse cardiac outcomes in underlying cardiac disease cases with COVID-19 pneumonia, and one should keep in mind the thromboembolic phenomenon that has been seen with COVID-19 pneumonia may be an aggravating event. Remdesivir is safe and can be used without any long-term effect on heart function.

Liver dysfunction

Another myth, commonly observed as liver dysfunction which is associated with Remdesivir use is irreversible and chances of permanent liver damage after use during the treatment of COVID-19 pneumonia in critical care setting. We have documented asymptomatic rise in liver enzymes as asparate amniotransferase/alanine aminotransferase < 5 times without rise in bilirubin or clinical jaundice in the majority of treated patients. Neither reported clinical jaundice, significant liver injury or liver failure in any of our patients. Studies[16],[17] also documented similar findings and there is no any significant live injury or dysfunction or liver failure with Remdesivir use in COVID-19 pneumonia cases. However, we recommend monitoring of liver functions in all Remdesivir treated cases with known liver disease patient such as alcoholic liver disease or cirrhosis due to any cause to prevent coagulation abnormalities, although long-term effects of Remdesivir on liver parenchyma are not very well documented or nil effect.

Rheumatological symptoms

Finally, we have documented rheumatological symptoms in post-COVID care settings like osteoarthritis and myopathy, and the myth is that majority of these patients consider this is related with Remdesivir use. Studies[18] confirmed that musculoskeletal symptoms can develop during coronavirus infections, as with other respiratory infections. By contrast, coronaviruses do not typically cause clinical arthritis but rather arthralgia and myalgia. Joint and muscle pain are quite rare (occurring in < 10% of cases) in the endemic coronaviruses, whereas arthralgia is reported in 15% of patients with COVID-19, and myalgia is even more frequent (44%).[18] There is no scientific evidence regarding the association of rheumatological manifestation with Remdesivir use, and whatever symptoms documented in follow-up or treated cases of COVID-19 pneumonia may be part of long COVID and not Remdesivir use.


  Clinical Lesson Top


Robust data are available regarding the usefulness of Remdesivir in COVID-19 pneumonia with variable efficacy and its use has been documented with shortened hospital stay without mortality benefit. Long COVID is the ultimate effect of longer viremia and toxemia with persistent inflammatory response and Remdesivir use may help in preventing it by curtailing timely viremia, and this is reality and myths should not prevent its use in currently ongoing pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available from: https://www.covid19treatmentguidelines.nih.gov/. [Last accessed on 2022 Feb 10].  Back to cited text no. 1
    
2.
CDSCO. Notice. Available from: https://www.cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division. [Last accessed on 2020 Nov 05].  Back to cited text no. 2
    
3.
US Food and Drug Adminitration. Veklury EUA Letter of Approval. Available from: https://www.fda.gov/media/137564/download. [Last accessed on 2020 Nov 05].  Back to cited text no. 3
    
4.
MOHFW, AIIMS, ICMR. Advisory for Rational use of Remdesivir for COVID-19 Treatment. Available from: https://www.mohfw.gov.in/pdf/AdvisoryforRationaluseofRemdesivirforCOVID19Treatment.pdf. [Last accessed on 2022 Feb 10].  Back to cited text no. 4
    
5.
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of covid-19 – Final report. N Engl J Med 2020;383:1813-26.  Back to cited text no. 5
    
6.
WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, et al. Repurposed antiviral drugs for covid-19 – Interim WHO solidarity trial results. N Engl J Med 2021;384:497-511.  Back to cited text no. 6
    
7.
Budhiraja S, Aggarwal M, Wig R, Tyagi A. Long term health consequences of COVID-19 in hospitalized patients from North India: A follow up study of upto 12 months. medRxiv 2021:1-24.  Back to cited text no. 7
    
8.
Thakare S, Gandhi C, Modi T, Bose S, Deb S, Saxena N, et al. Safety of remdesivir in patients with acute kidney injury or CKD. Kidney Int Rep 2021;6:206-10.  Back to cited text no. 8
    
9.
Adamsick ML, Gandhi RG, Bidell MR, Elshaboury RH, Bhattacharyya RP, Kim AY, et al. Remdesivir in patients with acute or chronic kidney disease and COVID-19. J Am Soc Nephrol 2020;31:1384-6.  Back to cited text no. 9
    
10.
Aranjani JM, Manuel A, Abdul Razack HI, Mathew ST. COVID-19-associated mucormycosis: Evidence-based critical review of an emerging infection burden during the pandemic's second wave in India. PLoS Negl Trop Dis 2021;15:e0009921.  Back to cited text no. 10
    
11.
Indian Council of Medical Research Evidence Based Advisory in the Time of COVID-19 (Screening, Diagnosis & Management of Mucormycosis). Available from: https://www.icmr.gov.in/pdf/ covid/techdoc/Mucormycosis_ADVISORY_FROM_ICMR_In_COVID19_time.pdf. [Last accessed on 2022 Jan 25].  Back to cited text no. 11
    
12.
John TM, Jacob CN, Kontoyiannis DP. When uncontrolled diabetes mellitus and severe COVID-19 converge: The perfect storm for mucormycosis. J Fungi (Basel) 2021;7:298.  Back to cited text no. 12
    
13.
Kumar J, Makheja K, Rahul F, Kumar S, Kumar M, Chand M, et al. Long-term neurological impact of COVID-19. Cureus 2021;13:e18131.  Back to cited text no. 13
    
14.
Bridwell R, Long B, Gottlieb M. Neurologic complications of COVID-19. Am J Emerg Med 2020;38:1549.e3-7.  Back to cited text no. 14
    
15.
Nabati M, Parsaee H. Potential cardiotoxic effects of remdesivir on cardiovascular system: A literature review. Cardiovasc Toxicol 2022;22:268-72.  Back to cited text no. 15
    
16.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Remdesivir. Available from: https://www.ncbi.nlm.nih.gov/books/NBK564049/. [Last updated on 2022 Feb 03].  Back to cited text no. 16
    
17.
Zampino R, Mele F, Florio LL, Bertolino L, Andini R, Galdo M, et al. Liver injury in remdesivir-treated COVID-19 patients. Hepatol Int 2020;14:881-3.  Back to cited text no. 17
    
18.
Schett G, Manger B, Simon D, Caporali R. COVID-19 revisiting inflammatory pathways of arthritis. Nat Rev Rheumatol 2020;16:465-70.  Back to cited text no. 18
    




 

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