COVID-19

These treatments are intended to prevent progression to severe disease in high-risk patients. They are given to patients within a few days of onset of mild to moderate COVID-19 who are ambulatory (or hospitalized for reasons other than COVID-19); treatment options (other than remdesivir) have not been studied in patients hospitalized for COVID-19.

Nirmatrelvir, an oral antiviral drug, given in combination with ritonavir, received Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA) for treatment of mild to moderate COVID-19 in adults and adolescents (≥ 12 years of age weighing ≥ 40 kilograms) who have positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19. The nirmatrelvir/ritonavir combination should be initiated as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset. The dosage is two 150-mg tablets of nirmatrelvir and one 100-mg tablet of ritonavir taken together orally twice a day for 5 days. This drug treatment is not authorized for use for longer than 5 consecutive days. (See also the FDA EUA Factsheet.)

Nirmatrelvir is a protease inhibitor that cleaves a SARS-CoV-2 protein and therefore inhibits the virus from replicating. Ritonavir is a strong cytochrome P450 (CYP) 3A4 inhibitor and acts as a boosting agent; it slows down the metabolism of nirmatrelvir, causing it to remain in the body for a longer duration at higher concentrations.

The nirmatrelvir/ritonavir combination was studied in a randomized controlled trial of 2,246 nonhospitalized symptomatic adults ≥ 18 years of age with a prespecified risk factor for progression to severe disease or ≥ 60 years of age regardless of prespecified chronic medical conditions. All patients had not received a COVID-19 vaccine, had not been previously infected with COVID-19, and had a laboratory confirmed diagnosis of SARS-CoV-2 infection. The nirmatrelvir/ritonavir combination given at ≤ 5 days after symptom onset reduced the proportion of people with COVID-19-related hospitalization or death from any cause through day 28 compared to placebo by 88% (0.8 vs. 6.3%) (1 Treatment references COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more ).

Using the nirmatrelvir/ritonavir combination in people with uncontrolled or undiagnosed HIV-1 infection may lead to HIV-1 drug resistance. The nirmatrelvir/ritonavir combination may cause liver damage, so caution should be exercised in patients with preexisting liver disease, liver enzyme abnormalities, or hepatitis. The drug is not recommended in patients with severe liver.

In patients with moderate renal impairment, which is an estimated creatinine clearance (also called estimated glomerular filtration rate or eGFR) of 30 to 60 mL/minute, the dose is reduced to 150 mg nirmatrelvir (one 150-mg tablet) with 100 mg ritonavir (one 100-mg tablet), with both tablets taken together twice a day for 5 days. Nirmatrelvir/ritonavir combination is not recommended in patients with severe kidney impairment (eGFR < 30 mL/minute).

Return of symptoms has been reported in some patients after use of nirmatrelvir/ritonavir, and PCR and antigen tests for SARS-CoV-2 can become positive again, even in patients who remain asymptomatic. Additional treatment is not currently recommended, but patients should be advised to re-isolate if rebound symptoms or tests occur. (See also CDC: COVID-19 Rebound After Paxlovid Treatment.)

The nirmatrelvir/ritonavir combination drug has a variety of serious known and possible drug interactions; concomitant drugs must be screened for these prior to initiation of treatment. For a list of these drug interactions see the FDA EUA Fact Sheet.

Remdesivir, an intravenous antiviral drug, is used to treat mild to moderate COVID-19 in adults and adolescents (≥ 12 years old and weighing ≥ 40 kilograms) who have positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19. It should be initiated as soon as possible and within 7 days of symptom onset. The dose of a 3-day course of remdesivir is 200 mg IV on day 1 and 100 mg IV on days 2 and 3. The course can be extended to 5 days for patients who progress to severe disease.

Remdesivir was studied for this indication in a randomized controlled trial of 562 nonhospitalized patients age ≥ 12 years of age with symptomatic COVID-19 at high risk for progression to severe disease and who had not received a COVID-19 vaccine. Remdesivir given for 3 days and started within 7 days of symptom onset reduced hospitalization or death rates through day 28 compared to placebo by 87% (0.7 vs. 5.3%) (2 Treatment references COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more ).

Molnupiravir, an oral antiviral drug, is a nucleoside analogue that works by introducing errors into the SARS-CoV-2 viral genome, which inhibits viral replication. It has received FDA EUA for treatment of mild to moderate COVID-19 in nonhospitalized adults ≥ 18 years of age who have positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe disease, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate. Molnupiravir should be initiated as soon as possible after diagnosis of COVID-19 and within 5 days of symptom onset. Molnupiravir is administered as four 200-mg capsules taken orally every 12 hours for 5 days. It is not authorized for use for longer than 5 consecutive days. (See also the FDA EUA Factsheet for Molnupiravir.)

Molnupiravir may have an effect on the emergence of new SARS-CoV-2 variants based on a theoretical concern; however, the risk is believed to be low based on available genotoxicity data and the limited 5-day treatment course. Molnupiravir is not authorized for use in patients < 18 years of age because it may affect bone and cartilage growth. Molnupiravir is not recommended for use during pregnancy because animal reproduction studies suggested that molnupiravir may cause fetal harm when administered to pregnant patients. Females of childbearing potential are advised to use a reliable method of birth control correctly and consistently during treatment with molnupiravir and for 4 days after the final dose. Males of reproductive potential who are sexually active with females of childbearing potential are advised to use a reliable method of birth control correctly and consistently during treatment with molnupiravir and for at least 3 months after the final dose.

Molnupiravir was studied in a randomized, double-blind, placebo-controlled clinical trial of 1433 nonhospitalized patients ≥ 18 years of age with mild to moderate COVID-19 at high risk for progression to severe COVID-19 and/or hospitalization and who had not received a COVID-19 vaccine. Molnupiravir given for 5 days and started within 5 days of symptom onset reduced hospitalization or death rates through day 29 compared to placebo (6.8 vs. 9.7%) (3 Treatment references COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more ).

Bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab are neutralizing anti-SARS-CoV-2 monoclonal antibody (mAb) therapies. The FDA recommended (April 22, 2022) against their use in treatment of COVID-19 because Omicron has become the dominant variant in the United States, and the new circulating Omicron subvariants are resistant to their neutralizing activity (see NIH: Anti-SARS-CoV-2 Monoclonal Antibodies). Bebtelovimab is a neutralizing anti-SARS-CoV-2 monoclonal antibody that retained activity against early Omicron variants but is not expected to neutralize the later and now predominant Omicron subvariants BQ.1 and BQ.1.1; therefore, effective November 30, 2022, bebtelovimab is not authorized for use in the US (see FDA Announces Bebtelovimab is Not Currently Authorized in Any US Region).

Recommended treatment options for severe infection include the antiviral drug remdesivir, the corticosteroid dexamethasone, and additional immunomodulatory drugs such as baricitinib, tocilizumab, and sarilumab. These may be used in combination, and treatment decisions should take into account the patient's phase of illness, often characterized by the degree of hypoxia and respiratory support.

Antiviral drugs are more likely to provide benefit earlier in the course when illness is a result of active viral replication, whereas anti-inflammatory and immunomodulatory therapies are better suited for later in the course when the host inflammatory response and immune dysregulation are driving the disease state. (Also see NIH: Therapeutic Management of Hospitalized Adults With COVID-19.)

For patients requiring supplemental oxygen but not additional respiratory support, treatment options include

The antiviral drug remdesivir is used to treat adult and pediatric patients ≥ 28 days of age and weighing ≥ 3 kg who require hospitalization for COVID-19. The recommended dosage for adults and pediatric patients weighing ≥ 40 kg is a single loading dose of 200 mg on Day 1 via intravenous infusion followed by once-a-day maintenance doses of 100 mg from Day 2 via intravenous infusion. The recommended dosage for pediatric patients ≥ 28 days of age and weighing 3 kg to less than 40 kg is a single loading dose of 5 mg/kg on Day 1 via intravenous infusion followed by once-a-day maintenance doses of 2.5 mg/kg from Day 2 via intravenous infusion. The recommended treatment duration is 5 days but is approved for use up to 10 days in patients who require invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO). Benefits of antiviral treatment in this group though are inconclusive.

In a large randomized clinical trial (ACTT-1), remdesivir was associated with earlier clinical improvement for patients requiring supplemental oxygen but not mechanical ventilation or other higher levels of support (4 Treatment references COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more ). This improved time to recovery was also observed in an outpatient randomized controlled trial (PINETREE) (2 Treatment references COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more ). However, benefit was not observed in 2 open-label trials (Solidarity [ 5 Treatment references COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more ] and DisCoVeRy [ 6 Treatment references COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more ]).

Overall, studies of remdesivir support its use early in infection (prior to days 7 to 10) when active viral replication is more likely to be contributing to illness. Remdesivir can also be considered in patients who are hospitalized but not requiring supplemental oxygen, although data are lacking in this population. Remdesivir is not recommended for patients with an eGFR < 30 mL/minute. Renal function should be monitored before and during remdesivir treatment. (See also the NIH treatment guidelines on remdesivir.)

The corticosteroid dexamethasone (at a dosage of 6 mg once per day for up to 10 days or until hospital discharge, whichever comes first) is generally recommended in patients with COVID-19 who require supplemental oxygen, but its use is not recommended in patients who do not require supplemental oxygen. Dexamethasone showed a survival benefit for those requiring supplemental oxygen or mechanical ventilation in the RECOVERY trial (7 Treatment references COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more ). Its benefit is likely to be greatest in patients whose illness is due to the inflammatory response from infection. If dexamethasone is not available, other corticosteroids (eg, prednisone, methylprednisolone, hydrocortisone) may be used.

The combination of remdesivir and dexamethasone is commonly used in hospitalized patients requiring supplemental oxygen within the first 10 days of illness when both viral replication and host inflammation may be contributing to the clinical presentation.

For patients requiring noninvasive ventilation (including high flow oxygen delivery systems), treatment options include

Additional immunomodulators include the JAK inhibitor baricitinib (or tofacitinib if unavailable) or the IL-6 inhibitor tocilizumab (or sarilumab if unavailable). These recommendations are based on subgroup analyses of numerous randomized (COV-BARRIER, ACTT-2) and open label (REMAP-CAP, RECOVERY) clinical trials that showed survival benefit with addition of one of these drugs in patients requiring this level of respiratory support. These drugs are potent immunosuppressants, and the potential benefit should be weighed against the additional immunosuppressive risk in patients with suspicion of a concomitant serious bacterial or fungal infection or at high risk for opportunistic infections due to an underlying immunosuppressive condition. See NIH treatment guidelines on immunomodulators for further details regarding appropriate patient selection for these therapies.

For patients requiring mechanical ventilation or ECMO, dexamethasone is recommended for all patients. The addition of tociluzumab should be considered for patients within 24 hours of admission to the intensive care unit (ICU).

Many therapies have been considered and are not currently recommended for the treatment or prevention of COVID-19:

An NIH panel concluded there is insufficient evidence to recommend either for or against the use of ECMO in adults with COVID-19 and refractory hypoxemia (see NIH COVID-19 Treatment Guidelines: Extracorporeal Membrane Oxygenation [May 31, 2022]).

Complications of COVID-19 illness should be treated as they arise. Hospitalized patients with COVID-19 may be at increased risk for thromboembolic events. Guidelines around managing this increased risk are continually evolving as data emerge (see NIH: The COVID-19 Treatment Guidelines Panel's Statement on Anticoagulation in Hospitalized Patients With COVID-19). Currently, therapeutic anticoagulation Anticoagulants All patients with deep venous thrombosis (DVT) are given anticoagulants and in rare cases thrombolytics. A number of anticoagulants are effective for management of deep venous thrombosis (see... read more should be considered in nonpregnant, hospitalized patients requiring supplemental oxygen but not intensive care if they have an elevated D-dimer and no serious bleeding risk. The risk of an adverse event from bleeding outweighs the potential benefit in critically ill patients. Pharmacologic anticoagulation prophylaxis should be considered for all other patients.

Drugs such as angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) therapy should be continued if needed for concomitant medical conditions but not started as treatment for COVID-19. There is no evidence that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is linked to worse outcomes, and either acetaminophen or NSAIDs can be used during the treatment of COVID-19.

Respiratory management of the nonintubated and intubated COVID-19 patient should take into consideration the tendency toward hypoxia. Nonpharmacologic adjunctive measures such as frequent repositioning and ambulation may be helpful. Therapeutic decisions should be made to best manage the patient but also consider the risk of exposure to health care practitioners and best use of resources. Intubation is a time of particular risk of health care practitioner exposure to infectious aerosols and should be done with extreme care.