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Treatment Options for Coronavirus Disease 2019 in Patients With Reduced or Absent Kidney Function

Published:September 17, 2020DOI:https://doi.org/10.1053/j.ackd.2020.09.001
      Coronavirus disease 2019, the disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was first identified in the Hubei Province of China in late 2019. Currently, the only role for therapy is treatment of the disease, as opposed to postexposure prophylaxis, however multiple clinical trials are currently ongoing for both treatment and prophylaxis. Treating coronavirus disease 2019 relies on two components; the first is inhibition of the viral entrance and replication within the body and the second is inhibition of an exacerbated immune response which can be seen in patients with severe disease. Many drugs have shown in vitro antiviral activity; however, clinical trials have not been as promising. This review summarizes the current data for the most commonly used drugs for coronavirus disease 2019 and will cover the unique factors that may affect the dosing of these medications in patients with CKD. While clinical trials are ongoing, most are in patients with normal kidney function. During a pandemic, when patients with CKD are at higher risk of both infection and death, it is imperative to include patients these patients in the clinical trials.

      Key Words

      • While active trials are ongoing, there is currently no known benefit of providing postexposure prophylaxis.
      • Active research is ongoing to determine the ideal treatment for coronavirus disease 2019, including antiviral therapy and immunomodulation.
      • Patients with reduced kidney function are in a high-risk category and may need special attention for drug dosing/interactions.
      In late 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of a familial cluster of pneumonia in the Hubei Province of China.
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      A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster.
      Human-to-human transmission was identified, and it spread worldwide with cases in the United States first identified in January 2020.
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      First case of 2019 novel coronavirus in the United States.
      On March 11, 2020, the World Health Organization declared coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2, a worldwide pandemic.
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      WHO declares COVID-19 a pandemic.
      As of August 1, 2020, the virus has killed more than 675,060 people worldwide with more than 20% of those recorded deaths within the United States.
      WHO
      Coronavirus disease (COVID-19) Situation Report -194.
      SARS-CoV-2 is a positive-strand RNA virus belonging to the Betacoronavirus that also contains severe acute respiratory syndrome coronavirus (SARS-CoV) (virus cause of SARS) and Middle East respiratory syndrome coronavirus (MERS-CoV).
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      The proximal origin of SARS-CoV-2.
      The virus uses its structural spike (S) protein to attack the target cells and binds to the host angiotensin-converting enzyme 2 protein. It is primed by the host transmembrane protease, serine 2 encoded by TMPRSS2 gene, to enter the cell using the host cell endosomes.
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      SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.
      Viral polyproteins are then synthesized and encode for the replicase-transcriptase complex. RNA is synthesized via its RNA-dependent RNA polymerases. Proteins are then synthesized together leading to completion of assembly and release of viral particles.
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      An understanding of the viral mechanism of infection helps to identify potential drug targets as illustrated in Figure 1.
      Figure thumbnail gr1
      Figure 1Mechanism of action of the drugs with possible antiviral activities. RDRP is RNA-dependent RNA polymerase. Abbreviation: ACE, angiotensin-converting enzyme.

      Role of Therapy

      Multiple randomized controlled trials are ongoing to determine the efficacy of several therapies targeting SARS-CoV-2. Currently, there are limited data to determine which patients require therapy and which patients improve without complications. Known risk factors for severe disease include CKD, chronic obstructive pulmonary disease, cancer, immunocompromised state from solid organ transplant, serious cardiac disease, type 2 diabetes mellitus, and obesity (body mass index >30).
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      Progressive hypoxia and high inflammatory markers including C-reactive protein and ferritin are also associated with progression of disease.
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      Despite recognizing these risk factors, it is unclear if treatment early in disease is associated with improved outcomes. While current practice seems to be targeting patients at highest risk of progression, limited data are also available to identify the ideal candidate for therapy. Table 1 summarizes suggested drug dosing adjustment based on reduced kidney function. The Infectious Disease Society of America (IDSA) guidelines have rapidly changed as new evidence has emerged but currently recommend only the use of remdesivir and corticosteroids outside of clinical trial.
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      Table 1Potential Therapies for SARS-CoV-2 and Dosage Adjustment for Reduced Kidney Function
      Drug NameMechanism of ActionPrecautionsKidney Implications
      Hydroxychloroquine/ChloroquineIncreases endosomal pH leading to defective protein degradation, endocytosis, and exocytosisQTc prolongation.

      Caution in G-6-PD
      G-6-PD: glucose-6-phosphate dehydrogenase deficiency.
      deficiency
      No kidney dose adjustment required
      RemdesivirInhibits RNA-dependent RNA polymeraseHepatic toxicityCaution in patients with CrCl
      CrCl: creatinine clearance.
      < 30 mL/min, not studied

      SBECD carrier can accumulate.
      Lopinavir/RitonavirInhibits the cleavage of viral proteinsDrug-Drug interactionsNo kidney dose adjustment required
      RibavirinContraindicated with CrCl <50 mL/min
      DexamethasoneAnti-inflammatoryNo kidney adjustment
      Tocilizumab/SarilumabAnti-IL-6Avoid in patients with active tuberculosisNo kidney dose adjustment recommended

      CrCl < 30 mL/min not studied
      JAK InhibitorsAnti-JAK inhibitorsIncrease risk of HSV and fungal infections.Variable based on the inhibitor.
      Abbreviations: IL, interleukin; JAK, Janus kinase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
      G-6-PD: glucose-6-phosphate dehydrogenase deficiency.
      CrCl: creatinine clearance.
      Multiple studies are actively being performed to assess the need for post-exposure prophylaxis including use of remdesivir, and convalescent plasma. Although early in the pandemic, there was some excitement for the use of hydroxychloroquine prophylaxis, a recent randomized, double-blind, placebo-controlled trial evaluating hydroxychloroquine as post exposure prophylaxis did show no difference between hydroxychloroquine therapy vs placebo, and therefore hydroxychloroquine, is unlikely to provide postexposure protection.
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      A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19.
      While other trials are currently pending, the IDSA currently recommends against the use of prophylaxis therapy outside of the clinical trial setting.
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      • et al.
      Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 [published online ahead of print April 27, 2020].

      Antiviral Considerations

      Chloroquine/Hydroxychloroquine

      Chloroquine is a widely used drug, commonly used for malaria therapy and autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus. Hydroxychloroquine is an analog of chloroquine with less drug interactions and less side effects. In SARS-CoV-2, chloroquine was hypothesized to block viral infection by increasing the endosomal pH required for virus/cell fusion leading to defective protein degradation, endocytosis, and exocytosis.
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      Review: hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19).
      ,
      • Vincent M.J.
      • Bergeron E.
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      • et al.
      Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.
      Studies performed in vitro showed that chloroquine and hydroxychloroquine both decreased the viral replication in a dose-dependent manner when given at treatment dosing; however, the inhibition rate was much lower when pretreated with hydroxychloroquine and chloroquine suggesting less of an effect if given as prophylaxis before infection.
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      In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
      Besides its antiviral properties, it also has some immunomodulation which could also be beneficial in treatment of COVID-19.
      Based on the above observations, chloroquine and hydroxychloroquine were used as early therapies in the treatment of COVID-19, and its use was further propagated by a small, retrospective, biased study from France with 36 patients, which showed decrease in viral burden and improved outcomes in patients treated with hydroxychloroquine.
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      Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.
      This small biased study received significant media coverage leading to high levels of nonevidence-based usage of hydroxychloroquine.
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      Swinging the pendulum: lessons learned from public discourse concerning hydroxychloroquine and COVID-19.
      Since then, larger population studies have been released with the majority showing no benefit in the use of chloroquine and hydroxychloroquine. Examples include a study from Borba and colleagues
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      Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial.
      comparing high-dose vs low-dose chloroquine that was discontinued early owing to toxicity in the higher dosage group with no benefit identified. A retrospective study from the Veterans Affairs looked at hospitalized patients who received hydroxychloroquine and showed no evidence that use of hydroxychloroquine reduced the risk of progression of disease including mechanical ventilation and death.
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      Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19 [published online ahead of print April 21, 2020].
      This study also showed a higher risk of death associated with the hydroxychloroquine group; even after a calculated propensity score, there is a bias as the hydroxychloroquine group represented the sickest patients.
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      Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19 [published online ahead of print April 21, 2020].
      Multiple large observational studies of New York also found no differences in outcomes between patients treated with hydroxychloroquine and those with no therapy.
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      Observational study of hydroxychloroquine in hospitalized patients with Covid-19.
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      • et al.
      Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state.
      In May 2020, the Lancet published an article which showed patients treated with hydroxychloroquine had higher mortality and no benefit for therapy. This study, however, was later retracted by authors given concern of the validity of the database.
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      RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis [published online May 22, 2020].
      Other studies including a New England Journal of Medicine article on the relationship between mortality and angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers was also retracted for using the same database.
      While the majority of the data associated with hydroxychloroquine has shown no difference, there was an article from Arshad and colleagues
      • Arshad S.
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      Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.
      that suggested a mortality benefit associated with the use of hydroxychloroquine and azithromycin. This was a retrospective study performed within 1 hospital system, but they found treatment with hydroxychloroquine alone improved mortality. More prospective clinical trials worldwide are ongoing; however, hydroxychloroquine is currently not recommended as therapy given the overwhelming negative data outside of this trial.
      While azithromycin has no antiviral effects, the Gautret
      • Gautret P.
      • Lagier J.C.
      • Parola P.
      • et al.
      Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.
      study also described 6 patients who received dual treatment with azithromycin and hydroxychloroquine with 100% of these patients having negative nasopharyngeal test for presence of virus by day 6 using polymerase chain reaction (PCR) technique. Multiple further studies have not shown any difference in virologic clearance or clinical outcomes when treated with both hydroxychloroquine and azithromycin.
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      No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection.
      Furthermore, studies looking at QTc prolongation associated with combination of hydroxychloroquine and azithromycin showed a prolonged QTc in at least 30% of patients, with 11% of patients having a QTc longer >500 ms.
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      QT interval prolongation and Torsade De Pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin.
      Based on these data, the current IDSA guidelines recommend against the usage of hydroxychloroquine with and without azithromycin outside of a clinical trial.
      While hydroxychloroquine is nondialyzable and kidney clearance accounts for 15-25% of total clearance of hydroxychloroquine; no dose adjustment is recommended in patients with CKD or those on dialysis.
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      Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases.

      Remdesivir

      Recently, there has been significant interest in the usage of remdesivir; in vitro activity has been noted against other RNA viruses including the Ebola virus, Marburg, MERS-CoV, and SARS-CoV.
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      • et al.
      Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.
      Remdesivir is an adenosine analog that inhibits RNA-dependent RNA polymerase by incorporating into the viral RNA chains causing premature termination.
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      • Mao C.
      • Luan X.
      • et al.
      Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir.
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      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      In vitro data show that it can inhibit SARS-CoV-2 infection effectively in human cell lines.
      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      In a nonhuman primate model, remdesivir prevented progression of disease both prophylactically and therapeutically.
      • de Wit E.
      • Feldmann F.
      • Cronin J.
      • et al.
      Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection.
      While multiple clinical trials are ongoing, some data have been released for remdesivir therapy. Compassionate usage data showed that patients with severe disease had a 68% improvement in oxygen-support class; however, this was just an observational study.
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      • Ohmagari N.
      • Shin D.
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      Compassionate use of remdesivir for patients with severe Covid-19.
      The Adaptive Covid-19 Treatment Trial (ACTT-1) was published in May 2020, which was a double-blind, randomized, placebo-controlled trial where they used intravenous remdesivir in hospitalized patients with COVID-19. With an enrollment of 1063, this was the largest clinical trial to date for remdesivir.
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      • Tomashek K.M.
      • Dodd L.E.
      • et al.
      Remdesivir for the treatment of Covid-19 - preliminary report [published online ahead of print May 22, 2020].
      This study showed a 31% faster recovery (11 days for patients treated with remdesivir compared with 15 days for patients who received placebo). There was also a trend to survival benefit (mortality rate of 7.1% for remdesivir and 11.9% with placebo), however not significantly different.
      • Beigel J.H.
      • Tomashek K.M.
      • Dodd L.E.
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      Remdesivir for the treatment of Covid-19 - preliminary report [published online ahead of print May 22, 2020].
      ,
      NIAID
      NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19.
      Based on these data, the IDSA guidelines currently recommend antiviral therapy over nonantiviral therapy. Multiple other clinical trials are in process.
      The pharmacokinetics of remdesivir in patients with kidney impairment has not been well studied. Clinical trials have included patients with a creatinine clearance greater than or equal to 30 mL/min and therefore no changes in dosing required.
      FDA
      Act Sheet for Health Care Providers Emergency Use Authorization (EUA) of Remdesivir (GS-5734TM).
      Currently, there are no dosing recommendations for individuals on dialysis and with those with a creatinine clearance of less than 30 mL/min. The biggest concern in the patients with impaired kidney function is the accumulation of the SBECD (sulfobutylether-β-cyclodextrin) carrier.
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      • Gandhi R.G.
      • Bidell M.R.
      • et al.
      Remdesivir in patients with acute or chronic kidney disease and COVID-19.
      SBECD is a large cyclic oligosaccharide whose accumulation in animal studies has shown to lead to liver necrosis and kidney tubular obstruction. SBECD is readily removed by hemodialysis and continuous renal replacement therapy. It is also speculated that a short course (eg, 5-10 days) is unlikely to cause such significant disease. Nevertheless, more data are needed in patients with kidney dysfunction.
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      Remdesivir in patients with acute or chronic kidney disease and COVID-19.

      Other Nucleotide Analogs

      Other drugs that affect the RNA polymerase include favipiravir, ribavirin, and EIDD-2801. Favipiravir is a pyrazine carboxamide derivative that inhibits the influenza viral RNA-dependent RNA polymerase. It currently holds approval for the treatment of influenza in both Japan and France.
      • Khambholja K.
      • Asudani D.
      Potential repurposing of Favipiravir in COVID-19 outbreak based on current evidence.
      In vitro studies have shown that favipiravir can inhibit viral proliferation.
      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      An open-label study from China compared favipiravir with combination of lopinavir/ritonavir. Both groups received aerosolized interferon (IFN)–a. This study showed improved chest imaging and viral clearance in the favipiravir group.
      • Cai Q.
      • Yang M.
      • Liu D.
      • et al.
      Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study.
      Multiple clinical trials worldwide are currently ongoing for favipiravir.
      Ribavirin is a guanosine analog. Studies on SARS-CoV showed some improvement of outcomes compared with historical outcomes when treated with ribavirin and lopinavir/ritonavir.
      • Chu C.M.
      • Cheng V.C.
      • Hung I.F.
      • et al.
      Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings.
      Another systemic review of 26 studies was inconclusive for the benefit of ribavirin for SARS-CoV.
      • Stockman L.J.
      • Bellamy R.
      • Garner P.
      SARS: systematic review of treatment effects.
      High concentrations of ribavirin however were needed for viral suppression.
      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      Further studies are needed. Use is contraindicated in patients with creatinine clearance of <50 mL/min.
      EIDD-2801 is an experimental nucleotide analog drug that inhibits SARS-CoV-2 replication in a cellular assay.
      • Sheahan T.P.
      • Sims A.C.
      • Zhou S.
      • et al.
      An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice.
      ,
      • Lu C.C.
      • Chen M.Y.
      • Chang Y.L.
      Potential therapeutic agents against COVID-19: what we know so far.
      It has been showed to be 2-10 times more potent than remdesivir in blocking SARS-CoV-2 replications in vitro.
      • Yin W.
      • Mao C.
      • Luan X.
      • et al.
      Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir.
      Currently, no clinical data are available on this drug, and it is currently in early clinical trials.

      Protease Inhibitors – Lopinavir/Ritonavir

      Lopinavir/ritonavir was originally developed for treatment of human immunodeficiency virus (HIV). It works by binding to protease and inhibiting the cleavage of viral proteins. Although SARS-CoV-2 has a different protease than HIV, studies have shown lopinavir/ritonavir has some in vitro activity against SARS-CoV-2.
      • Kumar S.
      • Zhi K.
      • Mukherji A.
      • Gerth K.
      Repurposing antiviral protease inhibitors using extracellular vesicles for potential therapy of COVID-19.
      While still in clinical studies, currently, there is no clear clinical benefit of lopinavir/ritonavir. Early case studies showed that the usage of lopinavir/ritonavir caused reduction in coronavirus viral load.
      • Lim J.
      • Jeon S.
      • Shin H.Y.
      • et al.
      Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT-PCR.
      In a small randomized, controlled, open-labeled trial of China, 199 patients were randomized 1:1 into standard therapy vs standard therapy with lopinavir/ritonavir. No differences were found in the clinical deterioration, time to clinical improvement, or duration of viral detectability. There was a numerically lower mortality rate, but the study was not powered to determine a significant difference in mortality.
      • Cao B.
      • Wang Y.
      • Wen D.
      • et al.
      A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19.
      Based on these studies, the IDSA guidelines recommend against the use of lopinavir/ritonavir outside of clinical trials.
      • Bhimraj A.
      • Morgan R.L.
      • Shumaker A.H.
      • et al.
      Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 [published online ahead of print April 27, 2020].
      Currently, as per the manufacturer’s guidance, no dosage adjustment is needed for patients with CKD including those on kidney replacement therapy.
      Because of the in vitro data, other protease inhibitors, including darunavir, were trialed, given a drug shortage of lopinavir/ritonavir. While unpublished, data released from Janssen, darunavir-cobicistat parent company, showed that darunavir has no in vitro activity against SARS-CoV-2.
      • Janssen
      Lack of evidence to support use of darunavir-based treatments for SARS-CoV-2.
      Therefore, darunavir-cobicistat is not recommended as therapy for COVID-19.

      Miscellaneous

      Many other drugs are currently under investigation for use in the treatment of COVID-19. Oseltamivir is a neuraminidase inhibitor used for influenza; however, neuraminidase is not found in the coronavirus, and although used in China and in some clinical trials, it is currently not recommended for usage.
      • Chen N.
      • Zhou M.
      • Dong X.
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      Nitazoxanide is a commercial antiprotozoal agent with a broad range of antiviral activity including coronavirus. In vitro, it also has some activity against SARS-CoV-2.
      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      No in vivo data have been published to this point.
      Ivermectin is a broad-spectrum antiparasitic agent that has also been shown to have some broad antiviral activity including activity against HIV-1, dengue virus, West Nile Virus, and influenza. In vitro studies have shown that ivermectin has some activity against SARS-CoV-2. No in vivo studies have been performed, and no clinical data are currently available.
      • Caly L.
      • Druce J.D.
      • Catton M.G.
      • Jans D.A.
      • Wagstaff K.M.
      The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro.

      Immunological Considerations

      While antiviral discovery and treatment is important, many of the pathological findings including acute respiratory distress syndrome are believed to be secondary to an extreme immune response. Early studies that compared patients with mild disease and patients with severe disease found that patients with severe disease had a higher ferritin, C-reactive protein, and interleukin (IL)-6, which lead to further treatment with these immunomodulators.
      • Ruan Q.
      • Yang K.
      • Wang W.
      • Jiang L.
      • Song J.
      Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.
      ,
      • Wang Z.
      • Yang B.
      • Li Q.
      • Wen L.
      • Zhang R.
      Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China.
      Symptoms described originally were suggestive of cytokine release syndrome that had been previously described in chimeric antigen receptor T cell (CAR-T cell) therapy.
      Cytokine release syndrome has been well described in CAR-T cell therapy. It is associated with fever, organ dysfunction including acute kidney injury and hepatitis, hypotension, and acute respiratory distress syndrome.
      • Lee D.W.
      • Santomasso B.D.
      • Locke F.L.
      • et al.
      ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells.
      Given the similarities between COVID-19 and cytokine release syndrome, immune-modulating agents have been attempted as discussed in the following.

      IL-6 Blockade

      Tocilizumab is a recombinant humanized monoclonal antibody that is directed against IL-6 receptor (IL-6R). Importantly, it binds both the IL-6R that is soluble and membrane bound. It was originally approved by the Food and Drug Administration for cytokine release syndrome associated with CAR T-cell therapy in 2019 based on some retrospective data.
      • Le R.Q.
      • Li L.
      • Yuan W.
      • et al.
      FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome.
      In the CAR-T cell therapy, they showed significant improvement in the hypotension, oxygenation, and organ dysfunction.
      • Le R.Q.
      • Li L.
      • Yuan W.
      • et al.
      FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome.
      Because of the correlation between cytokine release syndrome and COVID-19, tocilizumab was used early in the pandemic. An early observational study of 21 patients after treatment of tocilizumab showed improvement of fever, respiratory infection, and oxygen requirements; however, there was no control arm to this study.
      • Xu X.
      • Han M.
      • Li T.
      • et al.
      Effective treatment of severe COVID-19 patients with tocilizumab.
      A more recent retrospective case-control study of France showed a significantly lower mortality in patients treated with tocilizumab than those treated with standard of care.
      • Klopfenstein T.
      • Zayet S.
      • Lohse A.
      • et al.
      Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients.
      Multiple clinical trials are currently ongoing.
      Sarilumab is another IL-6 RA, which also binds the soluble and membrane-bound receptors. It is clinically improved for rheumatoid arthritis. Although no clinical data are present for sarilumab, multiple clinical trials are ongoing.
      Both of these drugs are not metabolized through the kidney, and therefore, no changes in dosing is required for patients with kidney dysfunction, although limited data on patients with creatinine clearance of less than 30 mL/min are available.
      FDA
      ACTEMRA® (tocilizumab) injection, for intravenous or subcutaneous use.
      IL-6 is an important cytokine in immunity against mycobacterium infections as well as hepatitis B infection, and therefore, testing for these infections is important before initiation of therapy if possible, and active disease is a contraindication to therapy. Other contraindications include greater than 1.5 times the upper limit of normal of the aspartate transaminase and alanine aminotransferase. Currently, the IDSA recommends use of tocilizumab only in the setting of a clinical trial.

      Janus Kinase Inhibitors

      The Janus kinase (JAK) inhibitors, ruxolitinib, tofacitinib, and baricitinib, are Food and Drug Administration approved for steroid-refractory graft vs host disease and rheumatoid arthritis.
      • Fragoulis G.E.
      • McInnes I.B.
      • Siebert S.
      JAK-inhibitors. New players in the field of immune-mediated diseases, beyond rheumatoid arthritis.
      Cytokine release syndrome is also treated with JAK inhibitors, spawning interest in their use for COVID-19 inflammatory response. These agents act through JAK1 and JAK 2 inhibition leading to inhibition of the IL-6 and IFN-g but also inhibit IL-2 and the IFN-a/b signaling cascade.
      • Ingraham N.E.
      • Lotfi-Emran S.
      • Thielen B.K.
      • et al.
      Immunomodulation in COVID-19.
      Clinical trials are currently ongoing looking at therapy with JAK inhibitors. Infection is a high concern for JAK inhibitors including increase risk of disseminated herpes simplex virus and fungal infections.
      • Bechman K.
      • Subesinghe S.
      • Norton S.
      • et al.
      A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis.
      ,
      • Gonzalez Vicent M.
      • Molina B.
      • Gonzalez de Pablo J.
      • Castillo A.
      • Diaz M.A.
      Ruxolitinib treatment for steroid refractory acute and chronic graft vs host disease in children: clinical and immunological results.

      Interferon

      Interferon has been used in a variety of treatment models including hepatitis C and MERS-CoV. In a nonhuman primate model infected with MERS-CoV, treatment with IFN-B1b showed improved clinical scores and lower mean viral load.
      • Chan J.F.
      • Yao Y.
      • Yeung M.L.
      • et al.
      Treatment with lopinavir/ritonavir or interferon-beta1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset.
      IFN-B1b was used some in China at the initiation of the COVID-19. A more recent small open-labeled randomized trial of Hong Kong compared IFN-B1b was combined with lopinavir-ritonavir and ribavirin and lopinavir-ritonavir alone. Study found that the triple antiviral therapy shortened the duration of viral shedding and shortened the hospitalization in patients with mild to moderate disease. Further studies are needed at this time to determine if any true benefit in severe disease.
      • Hung I.F.
      • Lung K.C.
      • Tso E.Y.
      • et al.
      Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial.

      Corticosteroids – Dexamethasone

      Corticosteroids usage in COVID-19 was originally controversial because some data in SARS patients found no difference between steroid usage and no steroid usage in clinical outcomes, although studies were small and mostly nonrandomized.
      • Stockman L.J.
      • Bellamy R.
      • Garner P.
      SARS: systematic review of treatment effects.
      One was a randomized, double-blind, placebo-controlled trial for patients with SARS that found delayed viral clearance if steroids were given at the first week of illness but found no clinical benefit of the steroids.
      • Lee N.
      • Allen Chan K.C.
      • Hui D.S.
      • et al.
      Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients.
      Another was a case-control trial that showed a higher risk of psychosis in patients treated with steroids and again no benefit noted.
      • Lee D.T.
      • Wing Y.K.
      • Leung H.C.
      • et al.
      Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study.
      Other studies have shown steroid use for SARS resulting in steroid induced diabetes mellitus and avascular necrosis. It was for these reasons corticosteroids were originally thought to be contraindicated in COVID-19 pneumonia.
      More recently, benefit has been suggested from steroid usage in patients with acute respiratory distress in COVID-19 pneumonia. In the recovery trial, the use of dexamethasone at 6 mg/day for 10 days had a significantly improved mortality for those requiring mechanical ventilation at the time of randomization (29.3% vs 41.4% mortality) and those requiring oxygen (23.3% vs 26.2%).
      The RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with Covid-19 - preliminary report [published online ahead of print July 21, 2020].
      This supported early observational studies that showed patients outside of acute respiratory distress had no improvement on steroids. Some studies even showed improved outcomes in progressive disease treated with methylprednisolone but for patients with acute respiratory distress.
      • Wu C.
      • Chen X.
      • Cai Y.
      • et al.
      Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.
      Clinical trials are still ongoing to evaluate use of steroids during acute respiratory distress syndrome in COVID-19 pneumonia. The IDSA now recommends use of steroids in patients requiring oxygen.

      Convalescent Plasma

      Prior use of convalescent plasma has been trialed for other viruses including Ebola virus, MERS-CoV, SARS-CoV, H5N1 avian influenza, and H1N1 influenza.
      • Shen C.
      • Wang Z.
      • Zhao F.
      • et al.
      Treatment of 5 critically Ill patients with COVID-19 with convalescent plasma.
      Trials during the pandemic influenza A (H1N1) in 2009 showed treatment with convalescent plasma resulted in reduction of respiratory tract viral load, serum cytokine response, and mortality.
      • Hung I.F.
      • To K.K.
      • Lee C.K.
      • et al.
      Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection.
      Of note, this was a cohort study and not a randomized control trial with control being patients who declined to get plasma. In COVID-19, a small case series of 5 patients who received convalescent plasma had improvement of disease including improved respiratory requirements and decreased in respiratory viral loads, and 3 of 5 patients were discharged by day 37 after transfusion.
      • Shen C.
      • Wang Z.
      • Zhao F.
      • et al.
      Treatment of 5 critically Ill patients with COVID-19 with convalescent plasma.
      Another case control study with 10 controls had a 30% mortality group in the control group as opposed to no deaths in the convalescent plasma therapy group.
      • Duan K.
      • Liu B.
      • Li C.
      • et al.
      Effectiveness of convalescent plasma therapy in severe COVID-19 patients.
      These case series were the basis of evaluation of convalescent plasma. Currently, there are multiple clinical trial ongoing using convalescent plasma for both treatment as well as prophylaxis therapy. These trials may also provide more data on its use in high-risk patient groups especially with CKD or kidney transplant recipients which may include remote risk of transmission of blood-borne diseases such as hepatitis B, hepatitis C, or HIV and of sensitization in a pretransplant recipient.
      World Health Organization
      Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion, as an empirical treatment during outbreaks.

      Vaccine Development

      Currently, there are no vaccines available for the SARS-CoV-2 virus; however, multiple vaccines are actively in clinical trials. These include vaccines using an adenovirus vector encoding the spike protein for SARS-CoV2 (ChAdOx1 nCoV-19), which currently has shown promise. Studies using rhesus macaques showed that after a SARS-CoV-2 challenge, macaques that were prevaccinated had lower viral burden and developed no signs of clinical pneumonia.
      • van Doremalen N.
      • Lambe T.
      • Spencer A.
      • et al.
      ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques [published online ahead of print July 30, 2020].
      This vaccine is currently in phase 3 trials in the United States.
      Another vaccine currently showing promise is the mRNA-1273. In phase 1 clinical trials, this vaccine induced anti-SARS-CoV-2 immune responses in all participants.
      • Jackson L.A.
      • Anderson E.J.
      • Rouphael N.G.
      • et al.
      An mRNA vaccine against SARS-CoV-2 - preliminary report [published online ahead of print July 14, 2020].
      Nonhuman primate studies have been performed using this vaccine as well, and they developed a robust SARS-CoV-2–neutralizing antibodies. These nonhuman primates also had significantly less pulmonary inflammation and reduced bronchoalveolar lavage viral loads.
      • Corbett K.S.
      • Flynn B.
      • Foulds K.E.
      • et al.
      Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates [published online ahead of print July 28, 2020].
      This vaccine and other variations of this vaccine are in clinical trials throughout the United States.

      SUMMARY

      Since the first cases of COVID-19, a variety of treatment options have been tested. Currently, standard of care is supportive care; however, multiple clinical trials are ongoing, and therefore, recommended treatment of these patients is changing rapidly. As more trials return, there is a need to look at the usage in all patients including those patients with kidney disease.

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