Home Guidelines & Resources Currently Available and Emerging Therapies for COVID-19

Currently Available and Emerging Therapies for COVID-19

Kelly M. Pennington, MD; and Eva M. Carmona, MD

This article covers therapies and medications currently in use or under trial for the treatment of patients with COVID-19.

  • Supportive care is the treatment standard for COVID-19.
  • While many therapies including antiviral and anti-inflammatory medications have been proposed to treat COVID-19, there is very little evidence to support the use of any therapy. Clinical trials to evaluate potential therapies are ongoing.
    • Remdesivir and favipiravir have shown promise as stand-alone therapy in in vitro models.
    • Clinical data have shown no benefit for lopinavir-ritonavir as stand-alone therapy.
    • Chloroquine and hydroxychloroquine have shown promise as effective therapy in limited clinical studies.
  • Glucocorticoids are not recommended for the treatment of COVID-19.
  • Interleukin-6 inhibitors are being studied as a therapy in critically ill patients with severe respiratory failure and elevated serum IL-6.
  • Convalescent plasma has been used with success in other viral infections. Clinical trials are ongoing to explore its efficacy in the treatment of COVID-19.

Supportive care is currently the standard treatment for COVID-19. Several clinical trials are ongoing to help establish the efficacy of various treatments, including antiviral therapies, re-purposed medications, and antiinflammatory medications. Because of the unknown benefit and limited medication availability, these medications should be used in consultation with an infectious diseases specialist and on a case-by-case basis. Preferably, these medications should be given as part of a research protocol to allow for further information to be garnered regarding their efficacy and safety.

Most patients with COVID-19 will develop only mild-moderate disease and will not require therapy beyond supportive care. However, a subset of patients will develop severe pulmonary disease and/or critical illness .1,2 For this subset of patients and patients with risk factors for developing severe disease, antiviral or repurposed medications may be considered. Risk factors for developing severe disease are as follows: age greater than 60 years, active cigarette smoking, immune-suppressing medications or conditions, chronic pulmonary disease, and heart disease. 1,2

Antiviral Therapy

Several antiviral medications have been proposed to treat COVID-19. These medications include remdesivir, lopinavir-ritonavir (with or without ribavirin), and favipiravir.

Remdesivir is a broad-spectrum antiviral agent that was initially developed to combat Ebola and Marburg viruses. It is a pro-drug nucleotide analogue with broad spectrum antiviral activity against RNA viruses such as coronavirus. This medication likely works by causing premature termination of viral RNA transcription. 3 In lung-epithelial cell cultures and mouse models, remdesivir has demonstrated activity against the viruses responsible for Middle Eastern Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), MERS-CoV and SARS-CoV-1, respectively. 4-6 Given the similarities between the viral structure of SARS-CoV-1 and SARS-CoV-2, it is speculated that remdesivir also has activity against SARS-CoV-2. Preliminary, non-peer reviewed data from in-vitro models also supports this. 7 Remdesivir has been used to treat select cases of COVID-19 with the results reported in case reports/ series, 8,9 but the clinical impact of remdesivir in COVID-19 remains unknown. Several clinical trials are underway. This medication appears well tolerated, but the side effect profile has not been clearly established.

Lopinavir-ritonavir is a combined protease inhibitor used for HIV treatment and post-xposure prophylaxis. Lopinavir has in-vitro activity against SARS-CoV-1. 10-12 Ritonavir, a potent cytochrome P450 inhibitor, is combined with lopinavir to increase the plasma concentration of lopinavir. An open-label, randomized trial to evaluate the efficacy and safety of lopinavir-ritonavir for COVID-19 was conducted in China. 13 This trial included 199 patients with confirmed moderate or severe COVID-19 (99 received lopinavir-ritonavir and 100 received supportive cares). No difference in mortality or viral load was observed between groups. 13 Secondary to a prior open-label study in 2004 that suggested lopinavir-ritonavir plus ribavirin reduced the risk of ARDS or death compared to ribavirin alone in SARS 10, optimism for lopinavir-ritonavir in combination with ribavirin as a potential therapeutic option in COVID-19 remains. If lopinavir-ritonavir in combination with ribavirin is efficacious in treating COVID-19, it has several potential advantages over remdesivir: these medications are already widely available, and they have a well-known side effect and drug interaction profile. Prior to using lopinavir-ritonavir, HIV testing should be completed as single agent therapy may promote HIV resistance.

Favipiravir is a pro-drug inhibitor of viral RNA polymerase. It has broad-spectrum activity against RNA viruses and was initially developed to treat neuraminidase-inhibitor resistant influenza.14 Data on in vitro and clinical activity of favipiravir for SARS-CoV-2 are sparse, but clinical trials are ongoing. On open-label study comparing favipiravir to lopinavir-ritonavir in patients with COVID-19 found a shorter viral clearance time and more rapid resolution of chest imaging abnormalities in patients receiving favipiravir. 15 This medication appears to be well-tolerated, but the side-effect profile is not well delineated, and the medication is not broadly available.

Both chloroquine and hydroxychloroquine have been proposed to treat COVID-19. Chloroquine is traditionally used to prevent and treat malaria. Both chloroquine and hydroxychloroquine are efficacious antiinflammatory agents used for the treatment of rheumatoid arthritis and lupus erythematous. These medications have potential broad-spectrum antiviral activity; although the exact mechanism of action is unclear, they are believed to interfere with viral-cell effusion. 16,17 China’s National Health Commission has included chloroquine and hydroxychloroquine in their treatment guidelines for COVID-19 secondary to reports of reduced disease progression and symptoms duration with these agents. 18 Primary data to support the use of these medications have not been released, but in vitro models do suggest activity against SARS-CoV-2. 7,19 Hydroxychloroquine was found to be a more potent inhibitor of SARS-CoV-2 in vitro than chloroquine. 20 A widely publicized, single-arm study in France of 20 patients with mild-moderate disease treated with hydroxychloroquine showed reduction in the nasopharyngeal viral load compared with patients from another center. 21 In six patients, azithromycin was used in conjunction with hydroxychloroquine. These patients had a more rapid reduction in viral load. Clinical benefit was not reported. No dosage or duration of therapy has been established for either of these medications. Hydroxychloroquine is also being proposed for post-exposure prophylaxis. Chloroquine is currently on national shortage. Chloroquine and hydroxychloroquine are generally well-tolerated but have the potential to cause QT prolongation and hemolytic anemia in patients with G6PD deficiency. Hydroxychloroquine can also cause visual disturbances. Clinical trials are currently ongoing to evaluate hydroxychloroquine for pre- and postexposure prophylaxis, as well as treatment.

Antiinflammatory Medications

Cytokine storm and viral evasion of the cellular immune system may play a key role in disease severity. 22 Cytokine storm can lead to and cause progression of ARDS. It has been proposed that a reduction in the host’s inflammatory response to SAR-CoV-2 in a select subgroup of patients may improve survival.

Glucocorticoids have previously been shown to have no benefit in SARS, MERS, and influenza, and observational data have shown increased viral shedding, increased mortality, and more secondary infections. 23-25 The World Health Organization has recommended against corticosteroids for the treatment of COVID-19 unless steroids are indicated for another reason. 26 In a retrospective cohort study of 84 patients with COVID-19 and ARDS, patients receiving methylprednisolone had a decreased risk of death, 27 suggesting that a subset of patients with severe COVID-19 may benefit from corticosteroids. Ongoing research is being conducted to determine if corticosteroids may be beneficial in a subgroup of patients.

Tocilizumab and siltuximab are interleukin-6 inhibitors that are approved for the treatment of cytokine activation syndrome secondary to Chimeric Antigen Receptor T cell (CAR-T) therapy. 28 No studies have been completed to evaluate the effectiveness of tocilizumab or siltuximab in the treatment of severe COVID-19. As part of a clinical trial, one of the medications may be considered in critically ill patients with ARDS and elevated IL-6 levels because of the theoretical effect of cytokine storm on the progression of ARDS and multiorgan failure. 29 These medications may increase the risk of life-threatening opportunistic infections. 30 Tocilizumab may have other serious side effects including transaminitis and bone marrow suppression. Siltuximab may cause edema, hypotension, and thrombocytopenia.

Convalescent Plasma

Convalescent plasma or immunoglobulins from recovered individuals have been used in the treatment of SARS, Ebola, and H1N1 influenza. 31-36 These therapies work to suppress viremia, enhance humoral response, and accelerate viral clearance from infected cells. 37,38 In SARS, convalescent plasma was associated with shorter hospital stays and lower mortality. 31-33 In H1N1, a prospective study showed a reduction in the risk of mortality in those treated with convalescent plasma 34 without significant adverse events. 35 Secondary to these prior successes, convalescent plasma has been proposed as a treatment option for COVID-19. 39 A recently published case series of five patients with severe COVID-19 and ARDS treated with convalescent plasma showed an overall improvement in clinical status with three patients discharged from hospital 51 to 55 days after transfusion. 40 Clinical trials are ongoing to determine if convalescent plasma may be a potential therapy for COVID-19.


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