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COVID-19 Therapeutics for Nonhospitalized Patients

Rajesh T. Gandhi, MD1; Preeti N. Malani, MD, MSJ2,3; Carlos del Rio, MD4

JAMA. Published online January 14, 2022. doi:10.1001/jama.2022.0335

Substantial progress has been made in therapeutics for nonhospitalized patients with COVID-19, but supply of and access to treatment remain limited. This Viewpoint summarizes currently available therapeutics for nonhospitalized patients in the setting of the Omicron variant including principles for equitable allocation.

Patients with mild or moderate COVID-19 are those who have respiratory and systemic symptoms but not hypoxia, tachypnea, or other complications that necessitate hospitalization.1 During this early phase of illness, viral replication is occurring and antiviral therapies are used to prevent disease progression, hospitalization, and death.

Antivirals target different stages of the SARS-CoV-2 life cycle. Anti–SARS-CoV-2 monoclonal antibodies bind to the viral spike protein, preventing attachment and entry into cells. Nirmatrelvir-ritonavir inhibits the SARS-CoV-2 main protease, which cleaves viral polyproteins into nonstructural proteins essential for replication. Molnupiravir and remdesivir target SARS-CoV-2 RNA replication: the former induces RNA mutagenesis leading to virus that is unable to replicate and the latter is a nucleotide prodrug that inhibits viral RNA polymerase. Because of mutations in the viral spike protein of the Omicron variant, most currently available anti–SARS-CoV-2 monoclonal antibodies have reduced activity. Nirmatrelvir-ritonavir, remdesivir, and molnupiravir, which target more conserved viral regions, are expected to remain active against Omicron.

Treatment Options in the Omicron Era

Sotrovimab. Three antispike monoclonal antibody products are currently authorized in the US for treatment of high-risk nonhospitalized patients with mild to moderate COVID-19 who are within 10 days of symptom onset: bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab.2 A preliminary non–peer-reviewed laboratory study demonstrated marked reduction in the activity of bamlanivimab/etesevimab and casirivimab/imdevimab against Omicron; by contrast, sotrovimab remained active.3 As a result, the National Institutes of Health (NIH) COVID-19 treatment guidelines recommend that sotrovimab, but not bamlanivimab/etesevimab or casirivimab/imdevimab, be used in areas with a high prevalence of Omicron.4

Nirmatrelvir-Ritonavir. Nirmatrelvir is co-formulated with ritonavir to inhibit CYP3A metabolism of nirmatrelvir and achieve therapeutic levels.5 In a phase 2/3 trial, 2246 nonhospitalized participants with COVID-19 who were at high risk of progression and within 5 days of symptom onset were randomly assigned to receive nirmatrelvir-ritonavir or placebo.6 Participants who received nirmatrelvir-ritonavir had an 88% reduction in hospitalization or death compared with the placebo group: 8 of 1039 (0.8%) vs 66 of 1046 (6.3%). On December 22, 2021, the US Food and Drug Administration (FDA) issued Emergency Use Authorization of nirmatrelvir-ritonavir for treatment of mild to moderate COVID-19 in adult and pediatric patients (age ≥12 years and ≥40 kg) who are at high risk for progression and within 5 days of symptom onset.

Because ritonavir inhibits CYP3A, it alters the metabolism of many other drugs. Nirmatrelvir-ritonavir should not be administered with medications such as amiodarone (and several other antiarrhythmic drugs), rifampin, or rivaroxaban. Other medications, such as calcineurin inhibitors, may need dose reduction or close monitoring. Medications such as statins may be temporarily stopped. Prior to prescribing nirmatrelvir-ritonavir for patients taking other medications, clinicians should consult with an experienced pharmacist to assess potential drug interactions.

Remdesivir. Remdesivir is FDA approved for treatment of hospitalized patients with COVID-19. In a randomized trial, 562 nonhospitalized patients with COVID-19 who were within 7 days of symptom onset and had at least 1 risk factor for disease progression were randomly assigned to receive intravenous remdesivir or placebo on 3 consecutive days.7 Participants who received remdesivir had a decreased risk of hospitalization compared with the placebo group: 2 of 279 (0.7%) receiving remdesivir and 15 of 283 (5.3%) receiving placebo. There were no deaths in either group. Based on these results, the NIH and Infectious Diseases Society of America COVID-19 treatment guidelines suggested remdesivir as an option for high-risk, nonhospitalized patients who are within 7 days of symptom onset.4,8 This outpatient use of remdesivir is currently off-label.

Molnupiravir. In a phase 3 trial, 1433 nonhospitalized adults with mild to moderate COVID-19 who had at least 1 risk factor for severe disease and who were within 5 days of symptom onset were randomly assigned to receive molnupiravir or placebo twice daily for 5 days.9 In the final analysis, participants who received molnupiravir had a 30% reduction in hospitalization or death compared with the placebo group (6.8% and 9.7%, respectively). This efficacy was lower than that observed in an interim analysis; the reasons for this difference are not clear.

Because of its mechanism of action, there have been theoretical concerns that molnupiravir may cause mutations in human DNA10 or hasten development of new viral variants. The FDA concluded that the drug has a “low risk for genotoxicity” but is requiring the manufacturer to develop a process to evaluate genomic databases for new viral variants.

On December 23, 2021, the FDA issued an Emergency Use Authorization for molnupiravir for treatment of adults with mild to moderate COVID-19 who are at high risk for progression and within 5 days of symptom onset but only if other authorized therapeutic options are not “accessible or clinically appropriate.” Molnupiravir is not recommended during pregnancy and is not authorized for children. The FDA recommends that individuals of child-bearing potential should use contraception during treatment and for 4 days after the last dose, and that males of reproductive potential who are sexually active with females of child-bearing potential should use contraception during treatment and for at least 3 months after the last dose.

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