COVID-19: Treatments and Vaccines

Jennifer Babik, MD, PhD, San Francisco, CA

  • Clinical course and treatment overview
  • Antivirals
  • Immunomodulators
  • Convalescent plasma and antibodies
  • Vaccines

This audio lecture is part of a high-yield learning activity from AudioDigest’s Internal Medicine Library.

Educational Objectives ⟶

The goal of this program is to improve the clinical and therapeutic management of patients infected with COVID-19. After hearing and assimilating this program, the clinician will be better able to:
1. Develop an overall treatment strategy for hospitalized patients with COVID-19.
2. Select effective modalities to treat anxiety related to cognitive dysfunction.
3. Recognize the symptoms of withdrawal from benzodiazepines.
4. Consider pharmacokinetic and pharmacodynamics factors when planning withdrawal from benzodiazepines.
5. Develop plans to taper chronic use of benzodiazepines.

Written Summary ⟶

Clinical course of COVID-19 infection: during the first week of illness, patients show several initial symptoms of COVID-19, while in the second week, they suffer from dyspnea and are admitted to the intensive care unit (ICU) and require intubation; this matches the viral phase in the first week of illness and an immune phase in the second week; antiviral therapy is potentially more effective early in the disease and immunomodulators are so in the immune-inflammatory phase of the disease

Remdesivir: a nucleoside analog that inhibits the RNA-dependent RNA polymerase of SARS-CoV-2 (ie, COVID-19); remdesivir is contraindicated if patients have severe liver abnormalities and renal failure because of the cyclodextrin vehicle that comes with remdesivir

Randomized controlled trial from Wuhan: 237 adults with symptoms of COVID-19 infection for ≤12 days and with pneumonia were randomized to remdesivir vs placebo for 10 days; this trial was underpowered to detect clinical benefit

ACTT-1 study: a randomized controlled trial of >1000 adults with severe COVID-19 infection, defined by radiographic infiltrates, an oxygen saturation level of ≤94% on room air, or the need for supplemental oxygen or mechanical ventilation; patients were randomized to remdesivir vs placebo for 10 days; results — remdesivir shortened the recovery time from 15 to 10 days; it proved beneficial when given earlier during the illness (≤10 days) and even during adjustment for steroid use; it led to a decreased length of stay (10 vs 14 days) and 29-day mortality was lower in the remdesivir group (not statistically significant); it is unclear whether remdesivir has the most benefit if the patient is on supplemental oxygen only; therefore, the National Institutes of Health (NIH) does not recommend using remdesivir in patients who are under high-flow nasal cannula or mechanical ventilation

SIMPLE study: a randomized controlled trial of almost 400 patients with inclusion criteria similar to ACTT-1; there was no difference in efficacy between the group taking remdesivir for 5 days vs 10 days; very few patients were on mechanical ventilation and most patients can take the drug for 5 days; consider 10 days if the patient is mechanically ventilated and/or not improving

Study by Spinner et al (2020): open-label trial of almost 600 adults with moderate COVID (defined by radiographic infiltrates and saturation level of >94%); patients were randomized to 5 or 10 days of remdesivir, although the 10-day group got a median of 6 days or standard of care; the results showed that by day 11, the 5-day remdesivir group had a modest improvement in clinical status vs standard of care; this improvement was not seen in the 10-day group, although it was significant at 14 and 28 days in post-hoc analysis; the mortality rate was very low (1%-2% for all groups; no statistically significant difference); there were concerns about the study design and uncertainty about the utility of remdesivir in the moderate COVID-19 group; as a result, the guidelines of the Infectious Diseases Society of America (IDSA) and NIH do not recommend using remdesivir in this group (controversial)

Emergency use authorization (EUA) for remdesivir: use was expanded to all inpatients, including all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19 infection, regardless of the severity of the disease; an EUA factsheet is given to the patient or the surrogate disclosing that this is an emergency use drug, not approved by the US Food and Drug Administration (FDA), and that the risks and benefits are not known; the patient can opt-in or opt-out; in this case, the available alternative (typically dexamethasone) should be given to the patient and family

Administration of remdesivir: 200 mg intravenous (IV) once, then 100 mg IV for 4 days with a daily assessment of brain natriuretic peptide level and liver function tests

Current guidelines: for patients hospitalized with a saturation level of >94%, the IDSA does not recommend use of remdesivir and the NIH considers data insufficient to recommend for or against use; at the speaker’s institution, symptomatic patients having infiltrates are treated with remdesivir; for patients who have oxygen saturation levels of <94% or require oxygen, IDSA recommends remdesivir; NIH recommends but does not strongly endorse use for all patients requiring high-flow nasal cannula, noninvasive mechanical ventilation, mechanical ventilation, and extracorporeal membrane oxygenation; at the speaker’s institution, these patients are treated with remdesivir

World Health Organization Solidarity trial: a multicenter, multicountry trial of >11,000 adults; patients were randomized to different treatment arms, including remdesivir, lopinavir, ritonavir, interferon monotherapy, hydroxychloroquine, and a control group; the results showed no difference in mortality, need for intubation, or length of stay from any drug vs control

Hydroxychloroquine: multiple randomized controlled trials showed no benefit but an increased risk for adverse effects; the FDA has revoked its EUA and the NIH and IDSA guidelines do not recommend using hydroxychloroquine

COALITION trial: it showed no clinical improvement with hydroxychloroquine, with or without azithromycin, and did show an increase in QT

RECOVERY trial: it showed no difference in mortality but an increased risk of the composite outcome of intubation and death with hydroxychloroquine; studies — Tang et al in BMJ showed no benefit in viral clearance; there was also an increased risk of adverse effects; similar results were seen in outpatient studies, in which no reduction in severity of symptoms and an increase in adverse effects were observed with hydroxychloroquine

Prophylaxis trials: showed no benefit in preventing infection after exposure; an increase in adverse effects was also shown

Lopinavir/ritonavir: postulated mechanism — acts against proteases of COVID-19 (controversial); trials — in observational trials it showed possible benefit in severe acute respiratory syndrome and Middle East respiratory syndrome; however, 2 trials failed to show any benefits regarding the time for improvement, mortality, or changes in viral load

Darunavir/cobicistat: used in patients with mild COVID-19 infection; patients got inhaled interferon with or without 5 days of darunavir/cobicistat; results showed no difference in viral clearance or time to defervescence; as a result, the IDSA guidelines recommend using lopinavir/ritonavir only in the context of a clinical trial and the NIH guidelines do not recommend using either lopinavir/ritonavir or other protease inhibitors

Steroids: there are four major randomized controlled trials and one meta-analysis on steroids

RECOVERY trial: a randomized controlled trial of >6000 patients with COVID-19 infection; patients had no contraindications of dexamethasone per the attending physician treating each patient; patients were randomized to 6 mg dexamethasone (IV or PO) vs usual care for 10 days or until discharge, whichever came first; results — 28-day mortality was lower in the dexamethasone group compared with the placebo group (23% vs 26%; statistically significant); mortality in the dexamethasone group was 17.8% in patients on room air vs 14% in the usual-care group; in patients who required supplemental oxygen, the mortality rate in the dexamethasone group was 23% vs 26% in the usual-care group; in patients on mechanical ventilation, mortality in the dexamethasone group was 29% vs 41% in the usual-care group; side effects of steroids, eg, hyperglycemia, infection, delirium, and impact on viral shedding were not reported

Additional studies of steroids: trials — include the CAPE COVID trial, the REMAP-CAP trial, and the CoDEX trial; all were stopped early (for ethical considerations) after results from the RECOVERY trial were released and were consequently underpowered; meta-analysis — a meta-analysis of 1700 patients in the intensive care unit infected with COVID-19 (92% of patients were intubated); 678 patients received steroids and 1000 patients received placebo or standard of care; the mortality was 32% in the steroid group vs 41% in the placebo or standard-of-care group; no increased risk for adverse effects was found

Recommendations for use of dexamethasone: the patients on room air should not receive dexamethasone, and those who are intubated or on supplemental oxygen should receive dexamethasone

Administration of dexamethasone: administer 6 mg (IV or PO) for 10 days or until hospital discharge, whichever comes first; patients should not be discharged on dexamethasone; if dexamethasone is not available, prednisone is acceptable to use (patients should be watched for infections, delirium, and hypoglycemia)

Baricitinib: JAK inhibitor and an anti-inflammatory drug that can inhibit the kinases that regulate COVID-19 endocytosis; it is currently an approved treatment for rheumatoid arthritis; IDSA provides no comment for use and NIH guidelines recommend against use except in clinical trials

Tocilizumab: anti-IL-6 receptor; case series reported benefits but had no control groups; retrospective studies and 2 meta-analyses gave conflicting results on mortality benefit; the COVACTA trial was a randomized controlled trial of 450 patients with severe COVID-19 infection; it showed no effect on clinical status or mortality and no difference in adverse effects; currently, the IDSA and NIH guidelines do not recommend its use in practice; the NIH allowed its use in clinical trials

Interferon: in a study, interferon-beta was given in triple therapy with ribavirin and lopinavir/ritonavir vs lopinavir/ritonavir alone; results showed that the triple-therapy group had more rapid viral clearance, and shorter symptom duration and length of stay; another randomized control trial used interferon-beta plus lopinavir/ritonavir vs placebo; patients who received combination therapy had lower mortality when given within 7 days compared with the placebo group; currently, the IDSA guidelines do not comment on use of interferon; the NIH recommends against its use except in clinical trials; IDSA and NIH do not recommend for or against its use in early mild to moderate COVID-19 infection because of the triple-therapy trial

Convalescent plasma: it is thought have an antiviral effect by containing neutralizing antibodies against COVID-19 infection; one trial of 103 patients with severe or life-threatening COVID-19 infection randomized patients to convalescent plasma vs standard therapy; the results showed that there was a possible signal for improvement in the severe group compared with the life-threatening group, suggesting a possibility that convalescent plasma is more effective earlier; there was a higher rate of viral clearance in the convalescent-plasma group; a lower mortality rate in the convalescent-plasma group was seen in observational and case-control studies

Convalescent Plasma Expanded Access Program: the initial report of 5000 patients showed transfusion reactions in <1% and possibly related deaths in 0.08%; this was considered no signal of toxicity beyond what was expected for plasma use in severely ill patients; this safety report now includes 20,000 patients and shows the same results

Efficacy of convalescent plasma: the initial 3-mo outcomes included lower mortality in patients transfused <3 days from diagnoses, both at 7-days and 30-days mortality; there was a mortality gradient based on how much donor neutralizing antibody was in the plasma they received; the FDA data cites lower mortality in nonintubated patients who had a higher donor titer

EUA for convalescent plasma: although it does not have randomized controlled trial data, the FDA issued an EUA for convalescent plasma; the logistic is similar to remdesivir treatment; hospitalized patients are provided a factsheet, are informed that it is investigational, and have a discussion about potential risks and benefits

Guidelines for convalescent plasma: benefits of plasma are unclear but it does appear to be safe; speaker’s recommendation — convalescent plasma is used in patients enrolled in clinical trials and who have very severe immunosuppression or are critically ill in the ICU with < 14 days onset; IDSA — recommended only in the context of a clinical trial; NIH — do not have sufficient data to recommend for or against

Neutralizing antibodies: current data include only press releases; the BLAZE trial — funded by Eli Lilly, using one or multiple antibodies against the spike protein in hospitalized patients; this trial showed a decreased need for visits to the emergency department and hospitalization, and a decrease in symptoms and viral load; the REGN (Regeneron) antibody cocktail — showed a reduction in viral load in seronegative patients and fewer medical visits

Vaccine trials: there are vaccines in phase 1, 2, and 3 trial rounds; all the trials with limited-approval vaccines are in China or Russia; there are no vaccines approved for full use in the United States (US); there are 5 trials in the US (2 on hold); timeline for vaccines is unclear

mRNA vaccine: the patient is given an mRNA that codes for a viral antigen that is delivered to human cells; it is taken up by the cell, leading to production of antigen in the cell and then antigen presentation by that cell and immune response

Test Your Knowledge ⟶

1. Which of the following factors is a contraindication for use of remdesivir in patients with COVID-19 infection? [L1]?

(A) Diabetes

(B) Severe liver disease

(C) Renal failure

(D) Both B and C****

The correct answer is D.  Remdesivir is a nucleoside analog that inhibits the RNA-dependent RNA polymerase of COVID-19; remdesivir was contraindicated if patients have severe liver abnormalities and renal failure associated with the cyclodextrin vehicle that comes with remdesivir

  

2. A meta-analysis of studies of patients with insomnia found that, compared with placebo, benzodiazepine use is associated with all the following findings EXCEPT:

(A) Longer duration of sleep

(B) Increased risk for cognitive changes

(C) Greater difficulty concentrating

(D) Reduced risk for fatigue

The correct answer is D.  A meta-analysis by Glass et al (2005) of studies comparing benzodiazepines with placebo for the treatment of insomnia in older adults found that sedative-hypnotic agents were associated with a slight improvement in sleep (eg, fewer awakenings, longer duration of sleep).  However, adverse events were twice as likely to occur as benefits.  Adverse events included psychomotor events, cognitive changes, fatigue, and difficulty concentrating.

 

3. In an 80-yr-old woman with chronic anxiety and mild depressive symptoms, early morning awakening is most likely secondary to which of the following causes?

(A) Age-related changes in sleep

(B) Chronic insomnia

(C) Cognitive impairment

(D) Major depressive disorder

The correct answer is D.  Early morning awakening is a common and classic symptom of major depressive disorder.

 

4. All the following are accurate statements about the management of anxiety associated with cognitive dysfunction EXCEPT:

(A) Patients can be referred for speech therapy at the first signs of objective deficit

(B) Cognitive therapy can give patients greater confidence

(C) Structuring daily routine helps to compensate for memory loss

(D) Pharmacologic agents are effective for managing anxiety as cognitive dysfunction progresses

The correct answer is D.  Speech and cognitive therapy and structuring routines are helpful in improving function and building confidence.  Pharmacologic agents are ineffective for treating anxiety related to cognitive dysfunction.

 

5. Use of benzodiazepines for as few as _______ can provoke symptoms of withdrawal.

(A) 2 wk

(B) 4 wk

(C) 6 wk

(D) 8 wk

The correct answer is B. Dependency on benzodiazepines can develop after 4 wk of use. Withdrawal at this point may trigger symptoms.

 

6. Which of the following factors is associated with an increased risk for seizures during withdrawal from benzodiazepines?

(A) Younger age

(B) Cardiovascular disease

(C) Concomitant use of alcohol and illicit drugs

(D) Psychiatric disease

The correct answer is C.  Risk for seizures during withdrawal from benzodiazepines is increased with concomitant use of alcohol or illicit drugs, history of a seizure disorder, and intake of supratherapeutic dosages.

 

7. Which of the following medications may increase plasma levels of alprazolam?

(A) Enalapril

(B) Alcohol

(C) Diltiazem

(D) Ibuprofen

The correct answer is C.  Both alprazolam and diltiazem are metabolized through the cytochrome P450 pathway.  Diltiazem can increase plasma levels of alprazolam.

 

8. Which of the benzodiazepines has no active metabolites?

(A) Alprazolam

(B) Clonazepam

(C) Diazepam

(D) Lorazepam

The correct answer is D.  Benzodiazepines with no active metabolites include lorazepam, oxazepam, and temazepam.

 

9. When considering withdrawal from a short-acting benzodiazepine, switching to which of the following agents may be beneficial?

(A) Lorazepam

(B) Diazepam

(C) Loprazolam

(D) Alprazolam

The correct answer is A.  Withdrawal from a short-acting benzodiazepine is associated with lower trough levels and more pronounced withdrawal symptoms.  Switching to a long-term agent may be helpful to mitigate symptoms (eg, lorazepam, clonazepam).  While diazepam is a long-acting agent, its many active metabolites may worsen withdrawal symptoms.

 

10. Which of the following strategies is(are) recommended when tapering benzodiazepines?

1. Reducing the dose 10% to 25% every 1 to 2 wk

2. Dividing pills in half

3. Switching from an as-needed to a fixed dosing schedule

4. Scheduling benzodiazepine-free days

(A) 1,3

(B) 2,4

(C) 1,2,3

(D) 2,3,4

The correct answer is A.  In general, decreasing doses 10% to 25% every 1 to 2 wk is recommended.  In patients taking benzodiazepines on an as-needed basis, switching to a fixed dosage schedule is recommended.  In patients taking only 1 pill, cutting pills in half is not recommended.  Scheduling benzodiazepine-free days is not recommended because this may increase symptoms of withdrawal.

 

For more Coronavirus Resources & Tools from Wolters Kluwer
including UpToDate and Ovid



ADDITIONAL RESOURCES:

Other relevant information on COVID from NEJM Journal Watch and NEJM Group is freely available at the NEJM Covid-19 resource page.

AudioDigest presents these free lectures to contribute to the ACCME’s database of activities to promote the safe rollout of COVID-19 vaccines.





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