The Population Health and Medical Science Committee of the American College of Physicians (ACP) updates the living, rapid practice points on the treatment of adults with COVID-19 in an outpatient setting. Practice points are based on a living, rapid review done by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems.
Abstract
Description:
Evidence for the use of outpatient treatments in adults with confirmed COVID-19 continues to evolve with new data. This is version 2 of the American College of Physicians (ACP) living, rapid practice points focusing on 22 outpatient treatments for COVID-19, specifically addressing the dominant SARS-CoV-2 Omicron variant.
Methods:
The Population Health and Medical Science Committee (formerly the Scientific Medical Policy Committee) developed this version of the living, rapid practice points on the basis of a living, rapid review done by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems (Danube University Krems). This topic will be maintained as living and rapid by continually monitoring and assessing the impact of new evidence.
Practice Point 1:
Consider molnupiravir to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease.
Practice Point 2:
Consider nirmatrelvir–ritonavir combination therapy to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease.
Practice Point 3:
Do not use ivermectin to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.
Practice Point 4:
Do not use sotrovimab to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.
Although COVID-19 is no longer a global health emergency according to the World Health Organization and Centers for Disease Control and Prevention, it remains an ongoing health issue for which evidence continues to emerge addressing clinical dilemmas, such as the choice of treatment (1, 2). Management of most adults with COVID-19, especially those with mild to moderate disease, is increasingly occurring in the outpatient setting due to the availability of treatment options. This version (version 2) of the American College of Physicians (ACP) Population Health and Medical Science Committee’s (PHMSC) living, rapid practice points presents advice about the treatment of adults with confirmed COVID-19 in outpatient settings, regardless of SARS-CoV-2 vaccination status. Mutations of the SARS-CoV-2 virus are continuously emerging, and they affect how well treatments for COVID-19 work (3, 4). This version of the practice points evaluates evidence specific to the SARS-CoV-2 Omicron variant becoming the dominant variant of concern. Version 1 of these practice points was published on 29 November 2022 (5). Appendix Table 1 summarizes changes in the methods, and Appendix Table 2 summarizes changes in the practice point statements between version 1 and version 2. Table 1 (6–15) and Figures 1 and 2 (14, 16) summarize the current evidence.
Appendix Table 1.
What Has Changed Since the Last Version—Methods
| Methods | Version 1 | Version 2 |
|---|---|---|
| Key questions | Subgroups of interest for key question 1a: age, gender, and comorbid conditions | Added socioeconomic status as a subgroup of interest for key question 1a |
| Inclusion criteria: study design | Only included RCTs with no restriction on enrollment date | Added prospective and retrospective cohort studies as designs of interest that met the following criteria: • Sample size ≥5000 • Adjusted for all the following confounding factors: age, comorbid conditions, and vaccination status. RCTs and cohort studies enrolling participants on or after 26 November 2021 to focus on the SARS-CoV-2 Omicron variant |
| Inclusion criteria: treatments evaluated | Included: • Azithromycin (antibiotic) • Chloroquine or hydroxychloroquine, ivermectin, and nitazoxanide (antiparasitics) • Lopinavir–ritonavir combination therapy, molnupiravir, nirmatrelvir–ritonavir combination therapy, and remdesivir (antivirals) • Convalescent plasma • Corticosteroids • Bebtelovimab, casirivimab–imdevimab combination therapy, regdanvimab, sotrovimab (monoclonal antibodies) • Fluvoxamine (selective serotonin reuptake inhibitor) |
Added: • Niclosamide (anthelmintic) • Colchicine (antigout agent) • Chlorpheniramine (antihistamine) • Ensitrelvir, favipiravir (antivirals) • Metformin (biguanide) • Tixagevimab–cilgavimab combination therapy (monoclonal antibody) • Camostat mesylate (protease inhibitor) Removed: • Bebtelovimab (monoclonal antibody) |
| Inclusion criteria: comparisons | The only comparison was placebo | Added no treatment or usual care as comparisons |
RCT = randomized controlled trial.
Appendix Table 2.
What Has Changed Since the Last Version—Practice Points
| Treatments | Version 1: Evidence Before the SARS-CoV-2 Omicron Variant | Version 2: Evidence for the SARS-CoV-2 Omicron Variant |
|---|---|---|
| Antibiotic treatments | ||
| Azithromycin | Not supported | No eligible studies |
| Antiviral treatments | ||
| Ensitrelvir | Not evaluated | No eligible studies |
| Favipiravir | Not evaluated | No eligible studies |
| Lopinavir–ritonavir combination therapy | Not supported | No eligible studies |
| Molnupiravir | Supported | Supported |
| Nirmatrelvir–ritonavir combination therapy | Supported | Supported |
| Remdesivir | Supported | No eligible studies |
| Antiparasitic treatments | ||
| Chloroquine/hydroxychloroquine | Not supported | No eligible studies |
| Ivermectin | Not supported | Not supported |
| Nitazoxanide | Not supported | No eligible studies |
| Monoclonal antibodies | ||
| Bebtelovimab | No eligible studies | Not evaluated |
| Casirivimab–imdevimab combination therapy | Supported if considered effective against a SARS-CoV-2 variant or subvariant locally in circulation | No eligible studies |
| Regdanvimab | Supported if considered effective against a SARS-CoV-2 variant or subvariant locally in circulation | No eligible studies |
| Sotrovimab | Supported if considered effective against a SARS-CoV-2 variant or subvariant locally in circulation | Not supported |
| Tixagevimab–cilgavimab combination therapy | Not evaluated | No eligible studies |
| Other treatments | ||
| Camostat mesylate | Not evaluated | No eligible studies |
| Chlorpheniramine | Not evaluated | No eligible studies |
| Ciclesonide | Not supported | No eligible studies |
| Colchicine | Not evaluated | No eligible studies |
| Convalescent plasma | Not supported | No eligible studies |
| Fluvoxamine | Not supported | No eligible studies |
| Metformin | Not evaluated | No eligible studies |
| Niclosamide | Not evaluated | No eligible studies |
Table 1.
Evidence Summary for Treatment of Confirmed COVID-19 in Outpatient Settings (Version 2)
| Treatments Studies (Patients), n* | Outcomes† |
|||||||
|---|---|---|---|---|---|---|---|---|
| All-Cause Mortality | COVID-19–Specific Mortality | Recovery | Time to Recovery | Hospital Admissions Due to COVID-19 | Serious Adverse Events | Adverse Events | ||
| Treatments supported for the Omicron variant | ||||||||
| Antiviral treatments | ||||||||
| Molnupiravir vs. usual care/no treatment | ||||||||
| 1 RCT (n = 25 783) |
↔
Probably no difference (8) ●●○ |
No evidence |
↑
Probably improves by 62%‡ (8) ●●○ |
↓
Probably reduces by 6 d (8) ●●○ |
No evidence |
↔
Probably no difference (8) ●●○ |
No evidence | |
| 1 cohort (n = 54 217) |
?
Very uncertain (12) ○○○ |
No evidence | No evidence | No evidence |
?
Very uncertain (12) ○○○ |
No evidence | No evidence | |
| Nirmatrelvir–ritonavir combination therapy vs. no treatment | ||||||||
| 5 cohorts§ (n = 16 529–699 848) |
↓
Probably associated with a reduction ranging from 51% to 85%‡ (7, 10, 12) ●●○ |
No evidence | No evidence | No evidence |
↓
Probably associated with a reduction ranging from 24% to 60%‡ (7, 11, 12) ●●○ |
No evidence | No evidence | |
| Treatments not supported for the Omicron variant | ||||||||
| Antiparasitic treatments | ||||||||
| Ivermectin vs. placebo | ||||||||
| 1 RCT (n = 1344) |
?
Very uncertain (9) ○○○ |
No evidence | No evidence |
↔
Probably no difference (9) ●●○ |
No evidence |
?
Very uncertain (9) ○○○ |
↔
May be no difference (9) ●○○ |
|
| Monoclonal antibodies | ||||||||
| Sotrovimab vs. no treatment | ||||||||
| 1 cohort (n = 5205) |
↔
May be no association (6) ●○○ |
No evidence | No evidence | No evidence | No evidence | No evidence | No evidence | |
| Treatments with evidence of net benefit for SARS-CoV-2 variants before the Omicron variant | ||||||||
| Antiviral treatments | ||||||||
| Remdesivir | No evidence | |||||||
| Monoclonal antibodies | ||||||||
| Casirivimab–imdevimab combination therapy | No evidence | |||||||
| Regdanvimab | No evidence | |||||||
| Treatments with evidence of no net benefit for SARS-CoV-2 variants before the Omicron variant | ||||||||
| Antibiotic treatments | ||||||||
| Azithromycin | No evidence | |||||||
| Antiparasitic treatments | ||||||||
| Chloroquine/hydroxy-chloroquine | No evidence | |||||||
| Nitazoxanide | No evidence | |||||||
| Antiviral treatments | ||||||||
| Lopinavir–ritonavir combination therapy | No evidence | |||||||
| Other treatments | ||||||||
| Ciclesonide | No evidence | |||||||
| Convalescent plasma | No evidence | |||||||
| Fluvoxamine | No evidence | |||||||
| New treatments (version 2) with no evidence for the Omicron variant | ||||||||
| Antiviral treatments | ||||||||
| Ensitrelvir | No evidence | |||||||
| Favipiravir | No evidence | |||||||
| Monoclonal antibodies | ||||||||
| Tixagevimab–cilgavimab combination therapy | No evidence | |||||||
| Other treatments | ||||||||
| Camostat mesylate | No evidence | |||||||
| Chlorpheniramine | No evidence | |||||||
| Colchicine | No evidence | |||||||
| Metformin | No evidence | |||||||
| Niclosamide | No evidence | |||||||
RCT = randomized controlled trial.
* Total baseline sample sizes are reported. Analytic sample sizes may vary by outcome.
† ? very uncertain about the effect, ↑ effect increase, ↓ effect decrease, ↔ no difference in effect. Certainty of evidence: ○○○ = insufficient, any estimate of effect is very uncertain; ●○○ = low, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; ●●○ = moderate, further research is likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; ●●● = high, further research is very unlikely to change our confidence in the estimate of effect (13).
‡ Percentages represent the risk reduction determined from the hazard, odds, and/or risk ratios for the individual studies included in the living, rapid review (version 2) (14).
§ One study evaluating nirmatrelvir–ritonavir combination therapy versus no treatment reported results by age groups only, thereby contributing only to results for key question 1a and not key question 1 reflected in this table (15).
Figure 1. Evidence summary for treatment of confirmed COVID-19 in outpatient settings.
CoE = certainty of evidence; RCT = randomized controlled trial.
Figure 2. Evidence description*.
ACP = American College of Physicians; RCT = randomized controlled trial.
* Evidence search and assessment done by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems (Danube University Krems) (14). A search for evidence from 26 November 2021 to 2 March 2023 aimed to identify RCTs and cohort studies evaluating select primary treatment of persons with COVID-19 in the outpatient setting.
† See reference 16.
The intended audience for these practice points includes clinicians, patients, the public, and public health officials.
Practice Points Development Process
An overview of the PHMSC as well as details of ACP’s living and rapid development process, including signals for updating and retirement, and policy on disclosure of interests and management of conflicts of interest can be found in ACP’s methods articles (17, 18). Bimonthly literature surveillance is planned to identify and evaluate new evidence from published literature that meets eligibility criteria to maintain this topic as rapid and living (17). Rather than specifying a set interval for issuing updates, the PHMSC will update these practice points when evidence emerges that the committee believes warrants a change in the clinical advice. The PHMSC may determine that a topic does not require further updates and, therefore, may decide to retire the publication from rapid or living status. The PHMSC will publish an update alert in the journal reporting the change in status along with a brief rationale.
Living, Rapid Review
These practice points are based on version 2 of a living, rapid review funded by ACP and conducted by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems (Danube University Krems) to address the key questions (14). The search and inclusion criteria were modified to focus on the Omicron variant by limiting studies to only those enrolling patients on or after 26 November 2021, when the World Health Organization first described the Omicron variant (19, 20) (Appendix Table 1). None of the studies included in version 1 were eligible for inclusion in version 2 because of this new restriction.
Key Question 1: What are the benefits and harms of COVID-19 treatments in symptomatic and asymptomatic adult patients with a confirmed SARS-CoV-2 infection in the outpatient setting?
Key Question 1a: Do the benefits and harms vary by patient characteristics (age, gender, socioeconomic status, or comorbid conditions), type of SARS-CoV-2 variant, immunity status (prior SARS-CoV-2 infection, vaccination status, or time since infection or vaccination), symptom duration, or disease severity?
Treatments Evaluated
The living, rapid review (14) evaluated the following treatments for which advice is most needed to inform clinical decision making (an asterisk indicates newly added treatments since version 1). Some treatments may be used in the inpatient setting or as adjunctive therapies in practice. However, the living, rapid review only included studies if the treatment was the primary treatment that patients received in the outpatient setting.
Niclosamide* (anthelmintic)
Azithromycin (antibiotic)
Colchicine* (antigout agent)
Chlorpheniramine* (antihistamine)
Chloroquine or hydroxychloroquine, ivermectin, and nitazoxanide (antiparasitics)
Ensitrelvir*, favipiravir*, lopinavir–ritonavir combination therapy, molnupiravir, nirmatrelvir–ritonavir combination therapy, and remdesivir (antivirals)
Metformin* (biguanide)
Convalescent plasma
Corticosteroids
Casirivimab–imdevimab combination therapy, regdanvimab, sotrovimab, and tixagevimab–cilgavimab combination therapy* (monoclonal antibodies approved by the U.S. Food and Drug Administration or European Medicines Agency for treatment of COVID-19 as of 2 March 2023)
Camostat mesylate* (protease inhibitor)
Fluvoxamine (selective serotonin reuptake inhibitor)
Outcomes of Interest
The PHMSC reviewed core outcome sets for COVID-19 (21–24) and rated the following outcomes as critical: all-cause mortality, COVID-19–specific mortality, recovery, time to recovery, hospital admissions due to COVID-19, serious adverse events, and adverse events. There was no change in the outcomes evaluated from version 1 to version 2.
Summary of New Evidence
Table 1 summarizes the evidence for version 2 of the living, rapid review (14). Two randomized controlled trials were identified that compared treatments with placebo (9) or usual care (8), as well as 6 retrospective cohort studies that compared treatments with no treatment (6, 7, 10–12, 15). Of the 22 eligible treatments for version 2 of the practice points, only 4 have evidence that specifically addressed the Omicron variant: ivermectin (1 study [9]), molnupiravir (2 studies [8, 12]), nirmatrelvir–ritonavir combination therapy (5 studies [7, 10–12, 15]), and sotrovimab (1 study [6]). Of the 8 included studies, 5 were fair quality (6, 8, 10, 11, 15) and 3 were poor quality (7, 9, 12). Coronavirus disease 2019 was confirmed by diagnostic testing, usually a reverse transcriptase polymerase chain reaction or antigen test; when a test result was unavailable, a diagnosis code for COVID-19 or the order date for the treatment being studied was used as a proxy for COVID-19 diagnosis. None of the new studies reported enrolling patients on the basis of SARS-CoV-2 vaccination status or prior diagnosis of COVID-19. In studies providing information, the percentage of patients who were fully vaccinated (depending on country and time of study enrollment) ranged from 13% to 94%, and the percentage of patients with previous self-reported COVID-19 ranged from 7% to 15%. Among the 8 new studies, 2 (8, 9) included only symptomatic patients and 6 included patients within 5 days of symptom onset (7, 10–12, 15) or with early symptoms (6). In 6 of these studies, only patients with documented underlying conditions (11), patients with relevant comorbidities (8), or patients at risk for progression to severe disease (7, 10, 12, 15) were eligible to participate. Further, 3 of these studies explicitly reported enrolling patients on the basis of having mild (12) or mild to moderate COVID-19 (7, 11).
There were 5 new studies that informed key question 1a about the variability in benefits and harms based on patient characteristics and immunity status (8, 10–12, 15). Symptom duration and disease severity were not evaluated in the new studies, and type of SARS-CoV-2 variant was not applicable because this version of the practice points focused on the Omicron variant. We could not draw conclusions about how to tailor treatment advice to certain risk groups due to inconsistency in the studies (14).
Practice Points and Rationales (Version 2)
The practice points and new evidence are summarized in Table 1 and Figures 1 and 2. The practice points are primarily informed by evidence evaluating the predominance of the Omicron variant (14) while considering the evidence from version 1 of the living, rapid review (25) and contextual considerations, such as the availability of treatments. Table 2 (26, 27) provides the current dosage of supported treatment options from the U.S. Food and Drug Administration.
Table 2.
Dosages for Treatment Options*
| Antivirals | Dosages |
|---|---|
| Molnupiravir (26) | 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days |
| Nirmatrelvir–ritonavir combination therapy (27) | 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all three tablets taken together twice daily for 5 days Dose reduction for moderate renal impairment (eGFR ≥30 to <60 mL/min): 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet), with both tablets taken together twice daily for 5 days |
eGFR = estimated glomerular filtration rate.
* Based on information available as of 21 August 2023.
Treatments Supported for the Omicron Variant
The order in which treatments are listed does not imply prioritization for outpatient treatment of COVID-19.
Antiviral Treatments
Practice Point 1: Consider molnupiravir to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease.
New evidence for the Omicron variant suggests a net benefit of molnupiravir in patients for whom treatment is initiated within 5 days of symptom onset, which is consistent with version 1 of the practice points. New evidence showed that molnupiravir probably improves recovery and reduces time to recovery compared with usual care (moderate certainty). However, there is probably no difference in all-cause mortality (moderate certainty). Evidence for harms showed that there is probably no difference in the incidence of serious adverse events (moderate certainty). Evidence is very uncertain or lacking for other critical outcomes.
Practice Point 2: Consider nirmatrelvir–ritonavir combination therapy to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease.
New evidence for the Omicron variant suggests a net benefit of nirmatrelvir–ritonavir combination therapy in patients for whom treatment is initiated within 5 days of symptom onset, which is consistent with version 1 of the practice points. New evidence showed that nirmatrelvir–ritonavir combination therapy is probably associated with a reduction in all-cause mortality and hospital admissions due to COVID-19 compared with no treatment (moderate certainty). Evidence is lacking for other critical outcomes including harms.
Treatments Not Supported for the Omicron Variant
Antiparasitic Treatments
Practice Point 3: Do not use ivermectin to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.
New evidence for the Omicron variant is consistent with version 1 of the practice points that there is no net benefit of using ivermectin to treat COVID-19. New evidence showed that there is probably no difference in time to recovery (moderate certainty) and that there may be no difference in the incidence of adverse events (low certainty) for ivermectin compared with placebo. Evidence is very uncertain for all-cause mortality and serious adverse events and is lacking for other critical outcomes.
Monoclonal Antibodies
Practice Point 4: Do not use sotrovimab to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.
New evidence adds to information that sotrovimab is not effective against the Omicron variant (28). New evidence showed no net benefit; sotrovimab may not be associated with all-cause mortality compared with no treatment (low certainty). Evidence is lacking for other critical outcomes, including harms.
Treatments With Evidence of Net Benefit for SARS-CoV-2 Variants Before the Omicron Variant
Antiviral Treatments
Remdesivir.
No eligible studies evaluated the benefits and harms of remdesivir for the Omicron variant. Evidence from version 1 showed a net benefit of remdesivir as it may improve recovery and reduce hospital admissions due to COVID-19 (low certainty) with probably no difference from placebo in the incidence of adverse events (moderate certainty) before Omicron became the dominant SARS-CoV-2 variant. Therefore, clinicians should prioritize the use of other available treatments that show effectiveness against the Omicron variant.
Monoclonal Antibodies
Casirivimab–Imdevimab Combination Therapy.
No eligible studies evaluated the benefits and harms of casirivimab–imdevimab combination therapy for the Omicron variant. There was evidence of a net benefit of casirivimab–imdevimab combination therapy compared with placebo (reductions in time to recovery [high certainty] and hospital admissions due to COVID-19 [moderate certainty]) in version 1. Because monoclonal antibodies target the spike protein of the virus and the efficacy of using monoclonal antibody treatment for COVID-19 varies depending on the SARS-CoV-2 variant, Omicron and its subvariants are not expected to be susceptible to casirivimab–imdevimab combination therapy (28). Therefore, clinicians should prioritize the use of other available treatments that show effectiveness against the Omicron variant.
Regdanvimab.
No eligible studies evaluated the benefits and harms of regdanvimab for the Omicron variant. Despite evidence of a net benefit of regdanvimab compared with placebo (improvement in recovery [moderate certainty] with no difference in the incidence of adverse events [low certainty]) in version 1, monoclonal antibodies target the spike protein of the virus, and the susceptibility of regdanvimab to Omicron and its subvariants is uncertain. Therefore, clinicians should prioritize the use of other available treatments that show effectiveness against the Omicron variant.
Treatments With Evidence of No Net Benefit for SARS-CoV-2 Variants Before the Omicron Variant
Antibiotic Treatments
Azithromycin.
No eligible studies evaluated the benefits and harms of azithromycin for the Omicron variant. In version 1, evidence showed that harms outweighed no benefit of using azithromycin to treat COVID-19.
Antiparasitic Treatments
Chloroquine or Hydroxychloroquine.
No eligible studies evaluated the benefits and harms of chloroquine or hydroxychloroquine for the Omicron variant. In version 1, evidence showed that there was no net benefit of using hydroxychloroquine to treat COVID-19. Evidence was lacking in version 1 about the efficacy of chloroquine for all critical outcomes.
Nitazoxanide.
No eligible studies evaluated the benefits and harms of nitazoxanide for the Omicron variant. In version 1, evidence showed that there was no net benefit of using nitazoxanide to treat COVID-19.
Antiviral Treatments
Lopinavir–Ritonavir Combination Therapy.
No eligible studies evaluated the benefits and harms of lopinavir–ritonavir combination therapy for the Omicron variant. In version 1, evidence showed that harms outweighed no benefit of using lopinavir–ritonavir combination therapy to treat COVID-19.
Other Treatments
Ciclesonide.
No eligible studies evaluated the benefits and harms of ciclesonide for the Omicron variant. In version 1, evidence showed that there was no net benefit of using inhaled or intranasal ciclesonide to treat COVID-19.
Convalescent Plasma.
No eligible studies evaluated the benefits and harms of convalescent plasma for the Omicron variant. In version 1, evidence showed that there was no net benefit of using convalescent plasma to treat COVID-19.
Fluvoxamine.
No eligible studies evaluated the benefits and harms of fluvoxamine for the Omicron variant. In version 1, evidence showed that there was no net benefit of using fluvoxamine to treat COVID-19.
New Treatments (Version 2) With No Evidence for the Omicron Variant
There were no eligible studies evaluating the benefits and harms of the following new treatments (version 2 only) for the Omicron variant.
Antivirals
Ensitrelvir
Favipiravir
Monoclonal Antibodies
Tixagevimab–cilgavimab combination therapy
Other Treatments
Camostat mesylate
Chlorpheniramine
Colchicine
Metformin
Niclosamide
Clinical Considerations
The living, rapid review did not evaluate comparative effectiveness, meaning evidence does not show if one treatment is more effective than another treatment.
Risk stratification is an important step in the initial evaluation to decide the best approach to treatment of COVID-19 in the outpatient setting. The current definition of risk factors for progression to severe COVID-19 disease can be accessed from the Centers for Disease Control and Prevention’s website: www.cdc.gov/coronavirus/2019-ncov/your-health/risks-getting-very-sick.html.
Outpatient management of mild to moderate COVID-19 is appropriate for most patients. The decision to initiate treatment for COVID-19 in the outpatient setting should be personalized and based on clinical judgment using an informed decision-making approach with the patient on potential treatment benefits, harms, patient characteristics (such as risk factors, comorbid conditions, and disease severity), patient preferences, and social determinants of health.
Before initiating outpatient treatment for COVID-19, review treatment warnings and precautions as well as all medications and potential drug interactions.
Viral rebound of SARS-CoV-2 and the recurrence of COVID-19 symptoms have been reported in some patients completing treatment with nirmatrelvir–ritonavir combination therapy (29).
Evidence Gaps
More research evaluating the efficacy, effectiveness, and comparative effectiveness, as well as harms, of pharmacologic and biologic treatments of COVID-19 in the outpatient setting is needed, particularly in the context of changing dominant SARS-CoV-2 variants and subvariants.
The effectiveness of retreatment of COVID-19 in patients with previous infections is an area that requires further research.
Studies applying prespecified subgroup analyses are needed to assess whether the efficacy and effectiveness of treatments for COVID-19 used in the outpatient setting vary by patient characteristics (age, gender, socioeconomic status, or comorbid conditions), type of SARS-CoV-2 variant, immunity status (prior SARS-CoV-2 infection, vaccination status, or time since infection or vaccination), symptom duration, or disease severity.
Footnotes
This article was published at Annals.org on 19 September 2023.
* This paper, authored by Amir Qaseem, MD, PhD, MHA; Jennifer Yost, PhD, RN; George M. Abraham, MD, MPH; Rebecca Andrews, MD, MS; Janet A. Jokela, MD, MPH; Matthew C. Miller, MD; and Linda L. Humphrey, MD, MPH, was developed for the Population Health and Medical Science Committee. Individuals who served on the Population Health and Medical Science Committee from initiation of the project until its approval were Linda L. Humphrey, MD, MPH† (Chair); Adam J. Obley, MD‡ (Vice Chair); Elie A. Akl, MD, MPH, PhD‡; Rebecca Andrews, MD, MS†; Andrew Dunn, MD, MPH†; Mary Ann Forciea, MD‡; Ray Haeme†§; Janet A. Jokela, MD, MPH†; Devan L. Kansagara, MD, MCR‡; Rachael A. Lee, MD, MSPH†; Katherine Mackey, MD‡; Maura Marcucci, MD, MSc‡; Matthew C. Miller, MD†; Sameer D. Saini, MD, MS†; CDR Mark P. Tschanz, DO†; and Timothy J. Wilt, MD, MPH‡. Members of ACP Division of Clinical Policy: Kate Carroll, MPH‡; Itziar Etxeandia-Ikobaltzeta, PharmD, PhD†; Curtis Harrod, PhD, MPH†; Amir Qaseem, MD, PhD, MHA†; Tatyana Shamliyan, MD, MS†; Karla Umana, MPH†; and Jennifer Yost, PhD, RN†. Approved by the ACP Executive Committee of the Board of Regents on behalf of the Board of Regents on 26 June 2023.
† Author.
‡ Nonauthor contributor.
§ Nonphysician public representative.
Update Alerts: These practice points are based on a literature search through 2 March 2023. There is a plan for bimonthly literature surveillance, and the living, rapid review along with the practice points will be periodically updated.
References
- 1. World Health Organization. Statement on the fifteenth meeting of the IHR (2005) Emergency Committee on the COVID-19 pandemic. Accessed at www.who.int/news/item/05-05-2023-statement-on-the-fifteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic on 29 July 2023.
- 2. Centers for Disease Control and Prevention. End of the federal COVID-19 public health emergency (PHE) declaration. Accessed at www.cdc.gov/coronavirus/2019-ncov/your-health/end-of-phe.html on 29 July 2023.
- 3. Center for Disease Control and Prevention. Variants of the virus. Accessed at www.cdc.gov/coronavirus/2019-ncov/variants/index.html on 29 July 2023.
- 4. World Health Organization. Tracking SARS-CoV-2 variants. Accessed at www.who.int/activities/tracking-SARS-CoV-2-variants on 29 July 2023.
- 5. Qaseem A, Yost J, Miller MC, et al; Scientific Medical Policy Committee of the American College of Physicians. Outpatient treatment of confirmed COVID-19: living, rapid practice points from the American College of Physicians (version 1). Ann Intern Med. 2023;176:115-124. [PMID: ] doi: 10.7326/M22-2249 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Aggarwal NR, Beaty LE, Bennett TD, et al. Change in effectiveness of sotrovimab for preventing hospitalization and mortality for at-risk COVID-19 outpatients during an Omicron BA.1 and BA.1.1-predominant phase. Int J Infect Dis. 2023;128:310-317. [PMID: ] doi: 10.1016/j.ijid.2022.10.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Aggarwal NR, Molina KC, Beaty LE, et al. Real-world use of nirmatrelvir-ritonavir in outpatients with COVID-19 during the era of Omicron variants including BA.4 and BA.5 in Colorado, USA: a retrospective cohort study. Lancet Infect Dis. 2023;23:696-705. [PMID: ] doi: 10.1016/S1473-3099(23)00011-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Butler CC, Hobbs FDR, Gbinigie OA, et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2023;401:281-293. [PMID: ] doi: 10.1016/S0140-6736(22)02597-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Naggie S, Boulware DR, Lindsell CJ, et al; Accelerating Covid-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators. Effect of higher-dose ivermectin for 6 days vs placebo on time to sustained recovery in outpatients with COVID-19: a randomized clinical trial. JAMA. 2023;329:888-897. [PMID: ] doi: 10.1001/jama.2023.1650 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Schwartz KL, Wang J, Tadrous M, et al. Population-based evaluation of the effectiveness of nirmatrelvir-ritonavir for reducing hospital admissions and mortality from COVID-19. CMAJ. 2023;195:e220-e226. [PMID: ] doi: 10.1503/cmaj.221608 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Shah MM, Joyce B, Plumb ID, et al. Paxlovid associated with decreased hospitalization rate among adults with COVID-19 - United States. MMWR Morb Mortal Wkly Rep. 2022;71:1531-1537. [PMID: ] doi: 10.15585/mmwr.mm7148e2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Wong CKH, Au ICH, Lau KTK, et al. Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study. Lancet. 2022;400:1213-1222. [10.1016/S0140-6736(22)01586-0] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:401-406. [PMID: ] doi: 10.1016/j.jclinepi.2010.07.015 [DOI] [PubMed] [Google Scholar]
- 14. Sommer I, Ledinger D, Thaler K, et al. Outpatient treatment of confirmed COVID-19. A living rapid evidence review for the American College of Physicians (version 2). Ann Intern Med. 19 September 2023. [Epub ahead of print]. doi: 10.7326/M23-1626 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Arbel R, Wolff Sagy Y, Hoshen M, et al. Nirmatrelvir use and severe Covid-19 outcomes during the Omicron surge. N Engl J Med. 2022;387:790-798. [10.1056/NEJMoa2204919] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. The World Bank Group. World Bank country and lending groups. Accessed at https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups on 29 July 2023.
- 17. Qaseem A, Yost J, Forciea MA, et al.; Scientific Medical Policy Committee of the American College of Physicians. The development of living, rapid practice points: summary of methods from the Scientific Medical Policy Committee of the American College of Physicians. Ann Intern Med. 2021;174:1126-1132. [PMID: ] doi: 10.7326/M20-7641 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Qaseem A, Wilt TJ, Forciea MA; Clinical Guidelines Committee of the American College of Physicians. Disclosure of interests and management of conflicts of interest in clinical guidelines and guidance statements: methods from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2019;171:354-361. [PMID: ] doi: 10.7326/M18-3279 [DOI] [PubMed] [Google Scholar]
- 19. World Health Organization. One year since the emergence of COVID-19 virus variant Omicron. Accessed at www.who.int/news-room/feature-stories/detail/one-year-since-the-emergence-of-omicron on 29 July 2023.
- 20. Center for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. Accessed at www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html on 29 July 2023.
- 21. WHO Working Group on the Clinical Characterisation and Management of COVID-19 Infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020;20:e192-e197. [PMID: ] doi: 10.1016/S1473-3099(20)30483-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Jin X, Pang B, Zhang J, et al. Core outcome set for clinical trials on coronavirus disease 2019 (COS-COVID). Engineering (Beijing). 2020;6:1147-1152. [PMID: ] doi: 10.1016/j.eng.2020.03.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Seligman WH, Fialho L, Sillett N, et al. Which outcomes are most important to measure in patients with COVID-19 and how and when should these be measured? Development of an international standard set of outcomes measures for clinical use in patients with COVID-19: a report of the International Consortium for Health Outcomes Measurement (ICHOM) COVID-19 Working Group. BMJ Open. 2021;11:e051065. [10.1136/bmjopen-2021-051065] [PMID: ] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Tong A, Elliott JH, Azevedo LC, et al. Core outcomes set for trials in people with coronavirus disease 2019. Crit Care Med. 2020;48:1622-1635. [PMID: ] doi: 10.1097/CCM.0000000000004585 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Sommer I, Dobrescu A, Ledinger D, et al. Outpatient treatment of confirmed COVID-19. A living, rapid review for the American College of Physicians. Ann Intern Med. 2023;176:92-104. [PMID: ] doi: 10.7326/M22-2202 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. U.S. Food & Drug Administration. Fact sheet for healthcare providers: emergency use authorization for LAGEVRIOTM (molnupiravir) capsules. Accessed at www.fda.gov/media/155054/download on 29 July 2023.
- 27. U.S. Food & Drug Administration. Fact sheet for healthcare providers: emergency use authorization for PAXLOVIDTM. Accessed at www.fda.gov/media/155050/download on 29 July 2023.
- 28. National Institutes of Health. Anti-SARS-CoV-2 monoclonal antibodies. Accessed at www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/ on 29 July 2023.
- 29. National Institutes of Health. Ritonavir-boosted nirmatrelvir (Paxlovid). Accessed at www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/ritonavir-boosted-nirmatrelvir--paxlovid-/ on 29 July 2023.