Discussing Outpatient COVID-19 Treatments

The general progression of COVID-19 has led society into a whirlpool of clinical trials, data extrapolations, and literature critiques. Currently, highly effective vaccines from Pfizer, Moderna, and Johnson & Johnson have been introduced and have helped mitigate the spread of COVID-19; however, for the unvaccinated, as well as for the estimated millions of immunocompromised persons who are less likely to respond robustly to vaccination, treatment remains important.^1,2

Patients hospitalized with COVID-19 and requiring oxygen supplementation have been treated with a myriad of cocktails including steroids, antivirals, and monoclonal antibodies. Though treatments have not been delineated first, second, or third lines in the treatment of this virus, they establish a groundwork to stratify patients into treatment protocols. Contrary to the inpatient side, in the outpatient setting, monoclonal antibodies have had a role in the management of COVID-19 in this patient population.^1,2

Currently, the Infectious Diseases Society of America (IDSA) Guidelines on the Treatment and Management of Patients with COVID-19 recommend the use of bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab for mild to moderate outpatient cases of COVID-19. The problem that arises is the logistical issues involving procurement and the planning that goes into the administration of these monoclonal antibodies. Generally, patients are required to sit for an infusion (20-60 mins) and an observational period post-infusion (30-60 mins). This requires protective personal equipment, additional nursing requirements, and overall challenges for the health system from a logistics perspective.^1,2 New oral COVID-19 treatment alternatives provide simpler logistics and cost considerations overall.

The COVID-19 Treatment Guidelines published by the USA Health and Human Services recommends the use of bamlanivimab 700 mg plus etesevimab 1400 mg administered as an IV infusion or casirivimab 600 mg plus imdevimab 600 mg administered as subcutaneous (SQ) injections for post-exposure prophylaxis (PEP) for people who are at high risk of progressing to severe COVID-19 if infected with SARS-CoV-2 and who have the vaccination status and exposure history.³ Of note, in clinical trials, only bamlanivimab monotherapy was used but the Emergency Use Authorization (EUA) was the combination product. Bamlanivimab was approved based on clinical data from the BLAZE-2 trial. This was a randomized, double-blind, phase 3 trial that enrolled 74 skilled nursing and assisted living facilities in the US for a total of 1175 patients. The patients were randomized in a 1:1 ratio to receive an IV infusion of either bamlanivimab monotherapy, 4200 mg, or placebo. In the entire population, there was a lower incidence of mild or worse COVID-19 in the bamlanivimab arm than in the placebo arm (8.5% vs. 15.2%; OR 0.43; 95% CI, 0.28–0.68; P < 0.001).⁴ Moreover, in the resident subgroup, the incidence of mild or worse COVID-19 was significantly lower in the bamlanivimab arm than in the placebo arm (8.8% vs. 22.5%; OR 0.20; 95% CI, 0.08–0.49; P < 0.001).⁴ Based on these results, the FDA approved bamlanivimab/etesevimab under the EUA on September 2.

Casirivimab/imdevimab was approved based on data from a phase 3 randomized, double-blind, placebo-controlled trial conducted in the United States, Romania, and Moldova. 1505 patients were randomized 1:1 to receive casirivimab 600 mg plus imdevimab 600 mg or placebo administered as 4 SQ injections. Results found that the use of casirivimab/imdevimab showed a risk reduction in the risk of symptomatic SARS-CoV-2 infection when compared with placebo (81.4% vs. 7.8%; OR 0.17; P < 0.001).5 Researchers found this risk reduction to be consistent from weeks 1-4. Additionally, casirivimab/imdevimab was associated with a significant risk reduction compared to placebo for symptomatic and asymptomatic infections (66.4% vs. 14.2%; OR 0.31; 95% CI, 0.21–0.46; P < 0.0001).⁵ Based on these results casirivimab/imdevimab was granted an EUA by the FDA on November 21, 2020.

Molnupiravir (Lagevrio) is the first-ever investigational oral antiviral therapy for the treatment of COVID-19 in non-hospitalized adult patients. It is a potent ribonucleoside analog that blocks SARS-CoV-2 replication by acting as a competitive substrate of virally-encoded RNA-dependent RNA polymerase. Merck has applied for an FDA EUA, where it was previously reviewed on November 30.⁶ Molnupiravir was recently approved, on November 4, 2021, in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of COVID-19. This renders positive considerations as a step forward in treating COVID-19 with more conventional therapies. This therapy’s claim to fame is based on the interim analysis of the MOVe-OUT clinical trial.⁶ Additionally, preclinical studies found the drug to be active against the delta, gamma, and mu variants. A Merck-funded phase 3 trial that investigated the efficacy and safety of molnupiravir in non-hospitalized adult patients with mild to moderate COVID-19.⁶

In the planned interim analysis of this phase 3 trial, a total of 775 patients who were initially enrolled in the MOVe-OUT trial, a phase 3 study, was formatted by 385 in the molnupiravir and 385 in the placebo group. Results show that molnupiravir reduced the risk of hospitalization or death by approximately 50% in all subgroups. 28 patients (7.3%) in the molnupiravir group were hospitalized through day 29 vs. 53 patients (14.1%) in the placebo group who were either hospitalized or died (p= 0.0012). With an absolute risk reduction (AAR) of 6.8%, relative risk reduction (RRR) of 48%, and number needed to treat (NNT) of 15, this agent provides compelling data to support its use in the management of COVID-19. ⁶

PF-07321332, branded as Paxlovid, is an antiviral drug developed by Pfizer which acts as an orally active 3CL protease inhibitor. Co-administration with a low dose of ritonavir helps slow the metabolism, or breakdown, of PF-07321332 in order for it to remain active in the body for longer periods of time at higher concentrations to help combat the virus.⁷

On November 5, Pfizer released data based on an interim analysis of the Phase 2/3 EPIC-HR trial, claiming a significant reduction of hospitalizations and deaths. Similar to molnupiravir, this oral alternative looks to target non-hospitalized adult patients with COVID-19, who are at high risk of progressing to severe illness.⁷ The primary endpoint looked at hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset. The ERIC-HR trial showed patients who received Paxlovid resulted in 3/389 (0.8%) hospitalizations while individuals in the placebo arm reflected an endpoint of 27/385 (7.0%) hospitalizations. Of note, there were no deaths reported in the treatment arm however, 7 subsequent deaths were seen in the placebo group (p <0.0001). With an absolute risk reduction (AAR) of 6.2%, relative risk reduction (RRR) of 89%, and number needed to treat (NNT) of 17, this oral alternative adds to the growing surge of outpatient treatments in the management of COVID-19. In addition, similar reductions in COVID-19-related hospitalization or death were observed in patients treated within five and ten days of symptom onset. ⁷

Fluvoxamine, a selective serotonin reuptake inhibitor, has gained some popularity recently for its potential in the use of COVID-19. Currently, it is FDA approved for the treatment of obsessive-compulsive disorder and depression. In vitro models have demonstrated fluvoxamine to express anti-inflammatory genes, ICAM1, VCAM1, COX2, and iNOS.⁸ There was a prospective, nonrandomized, observational cohort study that evaluated fluvoxamine for the treatment of COVID-19. Late last year, a study was published in JAMA, outlining fluvoxamine to be effective vs placebo in preventing clinical deterioration in patients who were hospitalized with COVID-19 (0% vs 8.7%; 95 CI, 1.8%-16.4%;p=0.009).8,9

More recently in The Lancet, fluvoxamine was found to be effective in preventing hospitalization (defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital) vs placebo (11% vs. 16%; relative risk [RR] 0.68; 95% CI, 0.5-0.88). Although preliminary studies have demonstrated efficacy, the IDSA guidelines recommend the use of fluvoxamine only in the setting of a clinical trial similar to the HHS guidelines where there is insufficient evidence to recommend either for or against the use of ivermectin for the treatment of COVID-19.^10,11 To fully understand alternative treatments, more research needs to be done in a randomized controlled setting.

Another agent that has gained popularity in the media is ivermectin, for its possible role in COVID-19 treatment. Ivermectin is currently FDA approved for onchocerciasis and strongyloidiasis but is also used off-label for a variety of parasitic infections. In vitro studies have shown ivermectin to have anti-inflammatory effects. Most recently, there was a randomized, double-blind, placebo-controlled trial for the use of ivermectin vs. placebo for the treatment of mild COVID-19. Patients were randomized to get ivermectin 200 mg or placebo. Results showed no difference in time to resolution to resolution of symptoms vs placebo (10 vs. 12 days HR, 1.07; 95% CI, 0.87-1.32; p=0.53).5 COVID-19 symptoms were found in 82% of patients getting ivermectin vs. 79% in the placebo group by the end of week 3.¹¹ Other studies have demonstrated similar results in the use of ivermectin in COVID-19. Currently, the IDSA guidelines recommend against the use of ivermectin and the HHS guidelines mention there is insufficient evidence to recommend either for or against the use of ivermectin for the treatment of COVID-19.^1,2,11

Many outpatient treatments have been tested and studied, but whether these clinical-trial success stories will translate into a global game-changer in the fight against the pandemic isn’t yet clear. Even if lower-income countries can afford the medicine, they might not have the diagnostic capacity to treat patients early in the course of their illness, when treatment could make a difference.^1,8,11 Finally, vaccines are our first-line tool for preventing hospitalization, though outpatient oral options are important, herd immunity and primary vaccinations have consistently been shown to reduce the spread and virulence of this virus.

References

1. Lotfi M, Hamblin MR, Rezaei N. COVID-19: Transmission, prevention, and potential therapeutic opportunities. Clin Chim Acta. 2020;508:254-266. doi:10.1016/j.cca.2020.05.044
2. Cascella M, Rajnik M, Aleem A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). In: StatPearls. Treasure Island (FL): StatPearls Publishing; September 2, 2021.
3. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.
4. Cohen MS, Nirula A, Mulligan MJ, et al. Effect of bamlanivimab vs placebo on incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities: a randomized clinical trial. JAMA. 2021;326(1):46-55
5. O’Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV antibody combination to prevent COVID-19. N Engl J Med. 2021;385(13):1184-1195
6. Fischer W, Eron JJ, Holman W, et al. Molnupiravir, an Oral Antiviral Treatment for COVID-19. Preprint. medRxiv. 2021;2021.06.17.21258639. Published 2021 Jun 17. doi:10.1101/2021.06.17.21258639
7. Pfizer’s Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk Of Hospitalization Or Death By 89% In Interim Analysis Of Phase 2/3 EPIC-HR Study. Press Release. Pfizer. Media News Release. 2021; Published 2021 Nov 5
8. Rafiee L, Hajhashemi V, Javanmard SH. Fluvoxamine inhibits some inflammatory genes expression in LPS/stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat. Iran J Basic Med Sci. 2016;19(9):977-984
9. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(22):2292–2300
10. Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VC, Edwards KM, Gandhi R, Gallagher J, Muller WJ, O'Horo JC, Shoham S, Murad MH, Mustafa RA, Sultan S, Falck-Ytter Y. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Infectious Diseases Society of America 2021
11. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.