Oral Therapeutic Options to Prevent Disease Progression From COVID-19 in an Ambulatory Setting

ContagionContagion, February 2022 (Vol. 07, No. 1)

As the number of COVID-19 cases continues to rise, oral treatment options for at-home use are in demand to provide early intervention and reduce the progression to severe disease, hospitalization, and death.

COVID-19, caused by SARS-CoV-2, has been declared a global pandemic; cases have exceeded 352 million and 5.61 million deaths worldwide.1-3 Three vaccines have become available in the United States that demonstrate effectiveness against development of disease, hospitalization, and death.4-9 Despite vaccine effectiveness, only 74% of the US population has received at least 1 vaccine dose.10 Unvaccinated individuals and populations at high risk of severe disease continue to require hospitalization for COVID-19.11 Emergency use authorization (EUA) has been granted for various ambulatory COVID-19 treatment options; all require administration in a hospital or observational setting and parenteral administration. Monoclonal antibodies represent a treatment option for outpatients and have been shown to reduce the risk of hospitalization and death in high-risk patient populations.12-15 However, with the emergence of new variants, the efficacy of current vaccines and treatment options has waned, leaving vulnerable populations at higher risk of developing disease progression.9,13 There is a need for safe, effective oral treatment options that can be easily distributed in the outpatient setting, prevent progression or death, and retain effectiveness despite newly emergent variants. There are currently 3 oral treatment options that may be considered for the management of outpatient COVID-19 infection.


Fluvoxamine is an oral selective serotonin reuptake inhibitor indicated for the treatment of obsessive-compulsive disorder and off-label for other psychiatric disorders (Table). Although not a true antiviral medication, fluvoxamine has multiple proposed mechanisms in COVID-19. Fluvoxamine has a high affinity for the σ-1 receptor (S1R) that regulates cytokine production and reduces inflammatory events associated with COVID-19 via decreased cytokine production, an effect similar to other COVID-19 treatment options.16,17 Fluvoxamine’s other proposed mechanism to combat COVID-19 include decreased platelet aggregation, mast cell degranulation, and interference with viral entry into cells.16 Three randomized controlled trials (RCTs) have evaluated the use of fluvoxamine for COVID- 19. Lenze et al conducted a randomized, double-blind, placebo-controlled trial (NCT04342663) in nonhospitalized patients with confirmed COVID-19. The dose of fluvoxamine in the trial was increased on day 3 to 100 mg 3 times daily, to maximize affinity for S1R, and continued for a total of 15 days. The primary end point of clinical deterioration—defined as shortness of breath (SOB) or hospitalization for SOB or pneumonia and oxygen saturation less than 92% or requirement of supplemental oxygen to maintain saturation equal to a greater than 92%—was collected via phone from participants and a review of hospital records. Clinical deterioration occurred in 0 of 80 patients who received fluvoxamine compared with 6 of 72 (8.3%) patients who received placebo.18 The TOGETHER randomized, placebo-controlled trial (NCT04727424) evaluated the use of fluvoxamine in nonhospitalized patients at high risk for severe disease. A total of 1497 patients received fluvoxamine or matching placebo at a dose of 100 mg twice daily for 10 days. The primary outcome of referral for hospitalization or retention in a COVID-19 emergency setting for 6 hours or more up to 28 days after randomization was lower in the fluvoxamine group at 11% compared with 16% in the placebo group. Patients with more than 80% adherence to fluvoxamine were included in a per-protocol analysis and demonstrated a larger treatment benefit compared with placebo regarding the primary outcome and mortality.19 The rate of adverse effects (AEs) was similar in the fluvoxamine group compared to placebo in both trials with the most common being headache, nausea, and vomiting.18, 19

Overall, between the 2 RCTs there was a trend toward lower all-cause hospitalizations with fluvoxamine (9.3%) compared with placebo (12.4%), (RR, 0.75; 95% CI, 0.57-0.99).17 The STOP COVID 2 (NCT04668950) RCT aimed to assess unvaccinated adults at risk for clinical deterioration. The study enrolled more than 700 patients but was stopped for futility by the data safety monitoring board.20 Although guidelines currently give a recommendation for fluvoxamine to be used in a clinical trial and the third RCT was stopped for futility, the familiarity, safety, and low cost make it a possible option for nonhospitalized patients in areas without other treatment options.13,17


As of December 2021, the FDA has issued EUAs for 2 oral antiviral agents 21,22 that demonstrate a benefit for the treatment of outpatient COVID-19 (Table). Molnupiravir (MOV), developed by Merck and Ridgeback Biotherapeutics, is a ribonucleoside analogue that targets RNA-dependent RNA-polymerase, an enzyme responsible for replication of viral RNA. MOV is a prodrug converted by esterases to N 4-hydroxycytidine (NHC). NHC is phosphorylated inside cells, leading to mutation and impairment of viral replication. In vitro, NHC has a broad activity targeting multiple RNA viruses including MERS-CoV, SARS-CoV, and SARS-CoV-2. MOV activity in animal studies demonstrates a reduction in viral load, viral replication, and transmission of the virus.23-25 A phase 2A trial (NCT04405570) evaluating escalating doses of MOV in nonhospitalized patients exhibited a significant reduction in viral RNA isolation and increased clearance in the high dose compared with placebo. 26

MOV was assessed in a randomized, double-blind, phase 3 trial (NCT04575597) in high-risk, nonhospitalized, and unvaccinated adults with mild to moderate COVID-19 using MOV or placebo for 5 days. The primary efficacy end points of hospitalization or death were significantly lower with MOV compared with placebo by day 29. Signs and symptoms of COVID-19 were more likely to resolve and less likely to progress in the MOV group. AEs were similar between MOV and placebo; most reported were diarrhea, nausea, and dizziness.27

Nirmatrelvir and ritonavir (NIR/RTV; Paxlovid), developed by Pfizer, was studied in adult patients with COVID-19 at high risk for disease progression.28 NIR inhibits the main protease in SARS-CoV-2 that is responsible for viral replication. It is designed to work before viral replication occurs. NIR is coadministered with RTV, an HIV-1 protease inhibitor and CYP3A4 inhibitor, which allows for an increased concentration of the drug.29 In December 2021, Pfizer announced final results from its phase 2/3 EPIC-HR (NCT04960202) study. NIR/RTV was compared to placebo in a randomized, double-blind study of nonhospitalized, unvaccinated adults with at least 1 risk factor for progression to severe illness from COVID-19 or who were older than 60 years. When compared with placebo, patients who received NIR/RTV within 5 days of symptom onset had an 88% reduced risk of hospitalization or death through day 28. The rate of hospitalization or death was 8 of 1039 (0.8%) in NIR/RTV compared with 66 of 1046 (6.3%) placebo. No deaths occurred in the NIR/RTV group and 12 occurred in placebo. NIR/RTV demonstrated a 10-fold reduction in viral load compared with placebo by day 5 in 499 patients. The most common AEs were nausea, vomiting, diarrhea, and dizziness and were similar between treatment and placebo groups.28 RTV has the potential to cause significant drug-drug interactions and caution must be given to patients prescribed concurrent CYP3A4 substrates or inhibitors.30 NIR/RTV is being studied to evaluate the benefit in patients with standard risk and post exposure to COVID-19.28

Early treatment of COVID-19 with available agents could be a game changer in preventing hospitalization and reducing death in high-risk patients. These oral agents are intended to be used early in the course of infection, optimally within the first 5 days. Prompt testing at the first sign of symptoms or following exposure and administration of oral medications as soon as possible would provide patients with the greatest potential benefit. Although not a replacement for vaccination, the ease of distribution and short course make them a favorable option.

covid-19 therapies


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