The severity and rapid spread of COVID-19 (caused by SARS-CoV-2) have raised questions about the use of some drugs in patients with the disease and whether currently available drugs could be effective in preventing or treating it. Definitive answers are lacking, but some recommendations can be made. For additional information on specific drugs, see our table Treatments Considered for COVID-19.

ACES AND ARBS — Patients with cardiovascular disease are at increased risk of severe COVID-19. Some researchers have suggested that this increase in risk may be due to use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with diabetes, hypertension, or heart failure. The basis for this hypothesis is that ACE inhibitors and ARBs increase expression of ACE2 by epithelial cells in the lung, and pathogenic coronaviruses such as SARS-CoV-2 enter these cells via ACE2 receptors.1 Others have suggested, however, that ACE2 may protect against lung injury in coronavirus infection and that taking an ACE inhibitor or an ARB might be beneficial.2,3

There is some evidence from retrospective trials suggesting that use of an ACE inhibitor or an ARB in patients with hypertension who were hospitalized for COVID-19 was associated with similar or lower mortality rates compared to patients who were not taking a drug from either class prior to infection.4,5,6 Other studies suggest that use of an ACE inhibitor or ARB is not associated with an increased risk of acquiring SARS-CoV-2.7 Prospective randomized-controlled trials evaluating these drugs in patients with COVID-19 are in progress.

Multiple medical organizations have advised against stopping or starting these drugs to prevent or treat COVID-19 infection. Patients who are taking an ACE inhibitor or an ARB and subsequently develop COVID-19 should continue to take the drug.3,8

NSAIDS — The Health Minister of France has warned that use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin, and others) to reduce fever in patients with COVID-19 increases the risk of severe adverse events and recommended use of acetaminophen (Tylenol, and others) instead.9 There is no convincing evidence that NSAIDs are especially dangerous for patients with COVID-19,10 but they can cause GI bleeding, fluid retention, and renal dysfunction in any patient, which can be dangerous for the critically ill. Controlled trials are lacking, but acetaminophen is an effective antipyretic and in recommended doses is less likely than an NSAID to cause serious adverse effects in most patients. Use of an NSAID or acetaminophen for continual fever suppression may reduce the immune response and prolong viral shedding. Patients who are taking NSAIDs for other indications should not stop taking them.

REPURPOSED DRUGS — In the absence of any FDA-approved drugs for treatment of COVID-19, many clinicians have turned to existing drugs to prevent or treat the disease. Some drugs that have been tried based on hypotheses or limited evidence include neuraminidase inhibitors used to treat influenza, HIV protease inhibitors, ribavirin, interferon, chloroquine/hydroxychloroquine, and azithromycin.11 Corticosteroids, interleukin-6 (IL-6) inhibitors, and Janus kinase (JAK inhibitors) have been used to suppress the inflammatory response. Evidence supporting off-label use of any of these drugs for treatment or prevention of COVID-19 is limited.

Neuraminidase inhibitors (e.g., oseltamivir) are not expected to be effective for prevention or treatment of COVID-19 because SARS-CoV-2 does not contain neuraminidase.

In a recently published randomized, open-label clinical trial in 199 hospitalized patients with severe COVID-19 illness, addition of the HIV protease inhibitor combination lopinavir/ritonavir (Kaletra) to standard care was not statistically significantly more effective than standard care alone in rates of virologic suppression, clinical improvement, or mortality.12 The median time from symptom onset to randomization was 13 days. Whether the combination might be more effective when started earlier in the course of illness or in patients with less severe disease remains to be established. Lopinavir/ritonavir can cause GI adverse effects, skin eruptions, hepatotoxicity, pancreatitis, and QT interval prolongation,13 and it has the potential to interact adversely with many drugs.14 The NIH and the Society of Critical Care Medicine recommend against use of lopinavir/ritonavir in COVID-19 patients15,16 and the Infectious Diseases Society of America (IDSA) recommends its use only in the context of a clinical trial.17

In a phase 2, randomized, open-label trial in Hong Kong, 127 hospitalized patients (only 12-14% required oxygen supplementation) were randomized to treatment with a combination of lopinavir/ritonavir, interferon-beta, and ribavirin if they were admitted <7 days after symptom onset (interferon was omitted if they were admitted >7 days after illness onset). Patients who were treated with the combination had a shorter time to a negative nasopharyngeal swab test compared to a control group (7 days vs 12 days) and a shorter duration of hospitalization (9.0 days vs 14.5 days).18

Chloroquine and hydroxychloroquine (Plaquenil, and generics), with or without the macrolide antibiotic of azithromycin (Zithromax, and generics), have been widely used off-label for treatment of patients with COVID-19 based on limited data from small uncontrolled trials showing that these drugs can reduce viral load and shorten the duration of symptoms. Multiple observational and cohort studies have not found these drugs, taken alone or in combination, to be effective for treatment of COVID-19.19-22 Randomized, controlled trials documenting their efficacy for treatment or prevention are lacking and their use is associated with cardiac adverse effects including QT interval prolongation and torsade de pointes. Interactions between these drugs and others that also prolong the QT interval13 are a concern.23,24

Because of the dose-related risk of QT prolongation, torsades de pointes ventricular arrhythmia, and sudden death, the Infectious Disease Society of America (IDSA) recommend that patients with COVID-19 admitted to the hospital receive chloroquine or hydroxychloroquine only in the context of a clinical trial, and the NIH specifically recommends against the use of hydroxychloroquine plus azithromycin because of potential toxicities.15,17 The FDA has cautioned against the use of hydroxychloroquine or chloroquine to treat COVID-19 outside of the hospital setting.

Randomized clinical trials evaluating the efficacy of hydroxychloroquine for prevention, post-exposure prophylaxis, and pre-emptive treatment are ongoing25 and the National Institute of Allergy and Infectious Diseases (NIAID) has started a large randomized, controlled trial evaluating the combination of hydroxychloroquine and azithromycin for prevention of hospitalization and death due to COVID-19. The COVID-19 Global Rheumatology Alliance, which is collecting data on COVID-19 in patients with rheumatologic conditions, has reported that many patients in their registry who acquired SARS-Co-V-2 were taking hydroxychloroquine for a rheumatologic condition at the time of their diagnosis, suggesting a lack of efficacy of the drug for prevention of COVID-19 infection.

The WHO and CDC recommend that corticosteroids not be used routinely for treatment of COVID-19 because they may prolong viral replication; they are recommended for COVID-19 patients with other indications such as COPD exacerbations and septic shock.26,27 The IDSA advises against the use of corticosteroids in hospitalized COVID-19 patients with pneumonia and recommends corticosteroids only in the setting of a clinical trial for those with ARDS.17 Two small observational studies conducted in China suggest that use of methylprednisolone may be beneficial in severe cases of COVID with ARDS.28,29 Randomized, controlled trials in this patient population are needed.

Other immunomodulating drugs such as IL-6 inhibitors, such as tocilizumab (Actemra) and sarilumab (Kevzara) or JAK inhibitors, such as baricitinib (Olumiant), may mitigate the effects of cytokines released in response to the virus and limit lung damage in patients with severe disease. According to preliminary results of a French trial comparing tocilizumab plus standard treatment to standard treatment alone in 129 patients hospitalized (non-ICU) with COVID-19 and moderate or severe pneumonia, use of tocilizumab was associated with a lower rate of noninvasive or mechanical ventilation compared to placebo. A tocilizumab trial in the US and Canada in patients with severe COVID-19 pneumonia is underway. In a phase II study, use of sarilumab in patients with severe COVID-19 pneumonia was not associated with clinical improvement compared to placebo.30 A study in critically ill patients is in progress.

Until clinical trials establish the efficacy and safety of any drug for treatment of COVID-19, the CDC recommends supportive treatment and appropriate management of complications, such as ARDS and bacterial pneumonia.27 Patients should be asked to participate in clinical trials of direct and supportive treatments.31

REMDESIVIR — Remdesivir (Gilead), an investigational broad-spectrum IV antiviral drug that is active against SARS-CoV-2 and other coronaviruses in vitro and in animal models,32 is currently being studied in controlled trials for treatment of moderate and severe COVID-19. Information from patients who have been treated with remdesevir for COVID-19 through an earlier compassionate use program have recently been published.33 According to the report, among 61 hospitalized patients with an oxygen saturation ≤94% (57% of whom were on mechanical ventilation) who were treated with remdesivir, 68% showed improvement in oxygen support requirements and 57% were able to be extubated. According to the manufacturer, interim results of a randomized, placebo-controlled trial being conducted by the National Institute of Allergy and Infectious Diseases (NIAID) in patients hospitalized with COVID-19 who had evidence of lung involvement have shown that use of remdesivir was associated with a faster time to recovery (11 days vs 15 days with placebo: p<0.05) and a trend toward improved mortality rates (8.0% vs 11.6% with placebo; p=0.059).34 Results from the study in patients with moderate disease are expected in late May. According to Gilead, its two US trials will be ending by the end of May.

Gilead has stopped honoring requests for individual compassionate use of remdesivir, except for pregnant women and children ≤18 years old with severe disease. The FDA approved emergency use authorization on May 1; once the two US trials are closed, patients will only have access to the drug though one of these two pathways.

CONVALESCENT PLASMA — Passive antibody therapy using the apheresed serum of recovered patients (no residual virus, high titers of neutralizing antibodies), which has been used in other viral epidemics, may be an option for prevention or treatment of COVID-19.35 Limited data from the current COVID-19 outbreak in China suggest that use of convalescent plasma in severely ill patients can reduce viral load and improve symptoms.36,37 In the US, convalescent plasma can be used in the setting of a clinical trial or through an institutional expanded access protocol. The FDA has also granted emergency access for individual patients with serious or immediately life-threatening COVID-19 infection under an emergency Investigational New Drug application.38 Until a vaccine becomes available, convalescent plasma might be especially beneficial for prevention of infection in healthcare workers or family members of recently diagnosed patients.39

VACCINES — A safe and effective vaccine may be the best way to prevent SARS-CoV-2 transmission and infection. To date, no vaccine has been approved by the FDA, but more than 100 vaccines are in development globally and a few are being studied in humans after positive results in animals. A commercially available vaccine will likely not be available until 2021.

REFERENCES