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

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

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

NOVEL ANTIVIRALS FOR COVID-19

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.

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