Outpatient COVID-19 therapeutics reduce hospitalization and mortality

Matching the right patient to the right therapeutic at the right time

In late 2021 and early 2022, the Food and Drug Administration (FDA) granted emergency use authorizations (EUAs) for the treatment of outpatients with mild-to-moderate COVID-19 for nirmatrelvir/ritonavir (Paxlovid), molnupiravir, and sotrovimab. In January 2022, the FDA expanded the approval for remdesivir to include outpatients with mild-to-moderate COVID-19. This important news arrived on the heels of the omicron surge, with cases and hospitalizations across the United States and most of the world setting all-time records.

Across most health care systems, significant effort is being channeled towards mitigating this rapid increase in hospitalizations. While many of these efforts are focused on optimizing vaccination and implementation of innovative workflow-related solutions, multiple clinical studies support that some of these outpatient therapies are highly effective at reducing hospitalizations and death from COVID-19. There may also be potential benefits for repurposed drugs such as fluvoxamine and inhaled corticosteroids.

However, the demand for the most attractive of these new therapeutics is currently outpacing supply. Nirmatrelvir/ritonavir seems to be the agent with the highest efficacy and greatest ease of clinical use. However, its availability thus far has been quite limited and has led health systems to implement and deliver these critical treatments using a prioritization plan that aims to optimize benefit while ensuring equitable care.

Our large, regional health system received 60 treatment courses of nirmatrelvir/ritonavir as a first allocation which was distributed to the highest-risk patients. Our supply was depleted within 10 days. An additional challenge is that the delivery of outpatient therapies needs to be coordinated in a timely manner: for the oral agents (nirmatrelvir/ritonavir and molnupiravir), within five days of symptom onset; for IV remdesivir, within seven days; and for sotrovimab, within 10 days.

In addition to navigating the supply issues and ensuring timely initiation of treatment, each agent comes with its own workflow challenges. Furthermore, none have been compared directly in a randomized controlled trial or retrospective study. Clinicians will strive to nimbly match the right patient to the right therapeutic at the right time and to do so at a time when supplies are limited and rapidly changing and distribution is at times centralized and variable in different states/regions (see Table 1 for a summary of outpatient COVID-19 therapeutics). A thorough understanding of the issues associated with each medication and a method for prioritization will help with this process.

Current outpatient therapeutic options for mild/moderate COVID-19

Nirmatrelvir/ritonavir (Paxlovid)

Nirmatrelvir is an orally administered, viral-protease inhibitor, given in combination with ritonavir. Ritonavir is also a protease inhibitor, sometimes used as part of antiretroviral therapy for HIV to boost other protease inhibitors. Drug-drug interactions are a significant concern through alterations in CYP3A metabolism. Certain medications would be contraindicated (e.g., amiodarone, rivaroxaban, rifampin) or may need to be adjusted/monitored closely (e.g., calcineurin inhibitors) while on nirmatrelvir/ritonavir. The treatment dose for patients with normal renal function is three pills every 12 hours for five days, taken with or without food. Dose reduction is required for patients with an eGFR <60 mL/min and it is not recommended for use in patients with severe renal impairment (eGFR <30 mL/min) or severe hepatic impairment (Child-Pugh Class C). According to the EUA, this drug must be administered within five days of symptom onset to non-hospitalized patients. In the EPIC-HR trial, the use of nirmatrelvir/ritonavir in unvaccinated subjects with mild-to-moderate symptoms and risk factors for progression to severe disease resulted in an 85% decrease in hospitalization/death.¹

Sotrovimab

Sotrovimab is a recombinant human IgG1k monoclonal antibody that binds to the spike protein receptor binding domain of SARS-CoV-2, inhibiting a step after virus attachment but prior to fusion of the viral and cell membranes. It is the only currently available monoclonal antibody with activity against the omicron variant and is given via a single 500 mg intravenous (IV) infusion over 30 minutes, with a required 60-minute post-infusion observation period per the EUA. This time for administration and observation creates capacity limitations (in addition to current supply constraints). It also requires cleanroom preparation, with a relatively short shelf life (24 hours under refrigeration and six hours at room temperature), limiting the opportunities for bulk preparation.

Sotrovimab is currently only authorized for the treatment of mild-to-moderate COVID in high-risk patients ≥12 years old and weighing ≥45 kg. According to the EUA, sotrovimab can be given up to 10 days from symptom onset, however, the available clinical data is in patients who received the infusion within five days of symptom onset, with 59% receiving treatment within three days of symptom onset. Therefore, it is best to give this agent as soon as possible after symptom onset. Despite the limitations associated with access, sotrovimab does not have any known drug interactions and is an option for those with severe renal or hepatic impairment that may not be eligible for other agents.

Like the other monoclonal antibodies, sotrovimab is produced using a Chinese hamster ovary cell line, to which some patients may object. In the COMET-ICE trial, sotrovimab was associated with a 79% reduction in hospitalization/death in patients with mild-to-moderate COVID-19 and at least one risk factor for progression.²

Remdesivir

Remdesivir inhibits the SARS-CoV-2 RNA-dependent RNA polymerase, which leads to decreased viral replication. It has been FDA-approved for the treatment of COVID-19 in hospitalized patients since October 2020, and just received an expanded indication for outpatient use based on the PINETREE study. This was a randomized, double-blind, placebo-controlled study in non-hospitalized patients with COVID-19 with symptom onset of <7 days and at high risk for progression to severe disease. Remdesivir, given as a three-day intravenous course (200 mg on day one, followed by 100 mg each on days two and three) was associated with an 87% decrease in progression to hospitalization or death as compared to placebo, with no increase in adverse effects.³

Remdesivir is currently not subject to the same supply constraints as nirmatrelvir/ritonavir. However, administration of this medication is challenging from a staffing/capacity management perspective and for patients for whom it may be difficult to get to an infusion center for three consecutive days. Due to these logistical constraints, this treatment option may be most favorable for patients that test positive for SARS-CoV 2, are hospitalized primarily for reasons other than COVID-19 with intended inpatient stays of three days or more, patients in skilled nursing facilities, or other long-term care settings, or patients who have already established visiting nurse or other home health care. Remdesivir is currently the only treatment option available to patients <12 years old, though the evidence is limited in this population and the PINETREE study only enrolled patients >12 years old. While this agent is generally well tolerated with few toxicity concerns, it is currently recommended to use with caution in patients with hepatic or renal impairment. The concern for renal toxicity is related to the presence of sulfobutylether-β-cyclodextrin (SBECD), but this is of less concern with a three-day course as only 12 gm of SBECD would be infused.

Molnupiravir

Molnupiravir is an oral antiviral that impairs SARS-CoV-2 viral replication by increasing the frequency of viral RNA mutations. Because of this mechanism of action, it is not recommended for use during pregnancy or breastfeeding, and individuals of childbearing potential must be advised to use effective contraception for the duration of treatment and four days following the last dose. It is given as four capsules every 12 hours for five days and can be given with or without food. As this drug is also approved under EUA, it must be given within five days of symptom onset to non-hospitalized patients. In the MOVE-OUT study, molnupiravir was associated with a 30% reduction in hospitalization/death when given to subjects with mild-moderate symptoms and risk for progression.⁴ The mutagenicity and concern for long-term effects coupled with the relatively low efficacy make this a less attractive option in comparison to the other available outpatient treatments.

It is important to note that previously mentioned studies of nirmatrelvir/ritonavir, molnupiravir, sotrovimab, and remdesivir were done in symptomatic, unvaccinated patients with non-omicron infections. It is unclear if there will be a similar benefit in the reduction of hospitalization/death in lower-risk patients, those who have been vaccinated, or those with omicron infection. In one unpublished report from the manufacturer in “standard risk” patients (low risk of hospitalization/death or vaccinated patients with risk for progression), nirmatrelvir/ritonavir was not associated with a reduction in the primary endpoint of sustained alleviation of symptoms. However, currently available unpublished results show a possible reduction in hospitalization in this lower-risk group (3/428 hospitalized with no deaths with nirmatrelvir/ritonavir compared to 10/426 hospitalized with no deaths with placebo, P=0.051).

Stewardship of therapeutics for mild/moderate COVID-19

Of the nearly one million cases diagnosed daily during the peak of the omicron surge in the U.S., there are not enough outpatient treatment courses available for those who qualify according to the EUA for the new oral antivirals and sotrovimab. According to some estimates, although the U.S. has ordered enough nirmatrelvir/ritonavir to treat about 20 million people, the first 10 million doses likely won’t be here until later in the spring, with only an estimated 250,000 courses being available by the end of January.⁵  In Massachusetts, the first allocation of nirmatrelvir/ritonavir was about 1100 courses for the entire state.⁶ Similar supply issues exist for sotrovimab and to a lesser extent, molnupiravir. While remdesivir supply is currently adequate, IV administration for three consecutive days poses significant logistical constraints.

To address the supply limitations, the Centers for Disease Control and Prevention (CDC) has recommended a prioritization schema for these new therapeutics, according to what is known regarding patient risk for progression to severe disease, need for hospitalization, and death. The approach has led to the development of priority tiers, with not fully vaccinated, elderly, obese, and immunocompromised patients given the highest priority to receive the most effective treatment in our health system (see Table 2). Additionally, when supply is limited, priority could be given to those with multiple risk factors. Some states and health care systems have developed lottery systems to allocate these scarce resources randomly among those at the highest risk.

To maximize the ability of these novel, limited therapeutics to improve patient outcomes and preserve hospital capacity through reduced admissions, a team-based approach will be needed to provide stewardship and make decisions about therapeutic utilization. These teams will have to coordinate decision making in an ethical manner and monitor use to be sure there is equitable distribution to vulnerable groups. These decisions need to be part of a highly efficient process where patient-level data (e.g., symptom duration, age, body mass index, degree of immunosuppression, GFR, pregnancy status, drug interactions) is processed against the background of current drug availability and the local health system’s staffing and infrastructure.

Lydia D’Agostino is an advisory board member for Gilead Science 

Dr. Benjamin Freda

Dr. Benjamin J. Freda is an internal medicine specialist in the division of hospital medicine and co-chair of the COVID therapeutics committee at Baystate Health, Springfield, Mass.

Lydia D’Agostino

Lydia D’Agostino is a clinical pharmacy specialist in infectious diseases with acute care pharmacy services at Baystate Health, Springfield, Mass.

Dr. Schimmel

Dr. Jennifer Schimmel is an infectious disease specialist in the division of infectious diseases, co-director of the antimicrobial stewardship program, and co-chair of the COVID therapeutics committee at Baystate Health, Springfield, Mass. She is also an assistant professor in the department of medicine, at the University of Massachusetts Chan Medical School-Baystate.

Table 1 Summary of Outpatient COVID-19 Therapeutics

 Table 2 Prioritization Groups for Outpatient Therapeutics

References

1. US Food and Drug Administration. Fact sheet for health care providers: emergency use authorization for Paxlovid. Accessed 2.2.22. https://www.fda.gov/media/155050/download
2. Gupta, A et al. Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody Sotrovimab. N Engl J Med. 2021 385(21):1941-50.
3. Gottlieb, R. L., et al. Early Remdesivir to prevent progression to severe Covid-19 in outpatients. N Engl J Med 2022 386(4):305-15.
4. Jayk Bernal A., et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2021:NEJMoa2116044. doi: 10.1056/NEJMoa2116044. Epub ahead of print.
5. Perrone M. COVID-19 pill rollout stymied by shortages as omicron rages. Medscape. 2022 Jan 13.
6. Gandhi R. CDC/IDSA clinician call: COVID-19 treatment updates plus the latest on omicron. 2022 Jan 10.