Current therapeutic options and resources to aid appropriate selection.
The growing number of therapeutics available to people with COVID-19 who are not sick enough to be hospitalized is welcome news. Staying up to date with rapidly evolving evidence is critical to ensure patients receive the right treatment at the right time. As of January 2022, there are numerous options for prevention and treatment of COVID-19 and the current variants of concern (VOC). This review will focus on SARS-CoV-2 monoclonal antibodies (mAB) (tixegevimab/cilgavimab and sotrovimab) and SARS-CoV-2 antiviral agents (molnupiravir, nirmatrelvir/ritonavir, and remdesivir).
Prevention
Although the mainstay of preventative therapeutics remains appropriate vaccination, certain high-risk individuals may benefit from additional passive immunity. Currently, the only agent approved for pre-exposure prophylaxis is Evusheld (tixagevimab/cilgavimab), a combination mAB delivered once as two separate intramuscular injections.
Tixagevimab/cilgavimab was approved for use in moderate-to-severe immunocompromised patients or those with contraindications for vaccination despite few of these patients being included in the current clinical trials. It received emergency use authorization (EUA) approval from the US Food and Drug Administration in December 2021. Tixagevimab/cilgavimab has a long half-life and provides adequate exposure up to six months after the injection. Evidence shows it prevents symptomatic COVID-19 infection in high-risk adults at 183 days compared to placebo. Of note, tixagevimab/cilgavimab remains active against the current VOC Omicron; however, its in-vitro activity is reduced 12-30 fold.
Treatment
The National Institute of Health developed guidance and a prioritization protocol for the use of several new treatment options that became available in late 2021, including Paxlovid (nirmatrelvir/ritonavir), sotrovimab, and molnupiravir. Many of these agents remain on extremely limited allocation. In these instances, prioritization should be given to those with the absolute greatest risk for progression to severe COVID-19. The US Department of Human Services (HHS) manages nirmatrelvir/ritonavir and sotrovimab allocations to states; allocation details may be found here.
The agent with first priority is nirmatrelvir/ritonavir (N/R) (Paxlovid). N/R was given first priority due to its perceived efficacy and comparative ease of administration. Nirmatrelvir is a protease inhibitor targeting MPRO leading to prevention of viral replication in all coronaviruses known to infect humans, including SARS-CoV-2. Ritonavir, a cytochrome P450 3A4 inhibitor, is included to boost the concentration of nirmatrelvir. This specific cytochrome is responsible for a majority of drug metabolism, and its inhibition leads to numerous drug-drug interactions. Each patient prescribed N/R must receive a medication review to assess for such interactions. An up-to-date drug interaction database, such as the Liverpool COVID-19 drug interaction database, should be used for screening. N/R comes in a combination dose pack and should be taken as three pills twice daily for five days. The dose of nirmatrelvir may need to be adjusted based on the patient’s kidney function. N/R is approved for treatment of COVID-positive patients within five days of symptom onset.
The agent with second priority is sotrovimab. This is a single mAB administered as an IV infusion approved for the treatment of COVID-19 within ten days of symptom onset. Currently, sotrovimab is the only approved mAB active against Omicron. Mutations to the virus render previously established mABs essentially useless. Sotrovimab has few drug interactions, and like N/R, remains on limited allocation due to supply issues.
The third agent recommended is remdesivir (RDV). Remdesivir was the first intravenous (IV) antiviral approved for the use of COVID-19. Remdesivir is a direct-acting nucleotide prodrug inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase. It has retained activity against all VOC and was recently studied in a reduced duration (three days) for use in outpatients at high risk for progression to severe COVID-19 within seven days of symptom onset. Outpatient use of RDV remains a logistical hurdle because it requires IV administration. However, the Centers for Medicare & Medicaid Services has published a J code (J0248) for outpatient infusion of RDV. This will likely aid reimbursement issues, though administration of three consecutive days of IV therapy is likely to remain difficult to coordinate.
The final agent recommended for treatment of COVID-19 presently is molnupiravir. Molnupiravir is a prodrug of a ribonucleoside with broad RNA antiviral properties; when incorporated into the elongating RNA thread, it leads to viral mutation and subsequent death. The agent was the first oral agent granted EUA approval for the use of outpatient COVID-19. It should be administered within five days of symptom onset. The dose is four capsules twice daily for five days. Molnupiravir is not expected to have many drug-drug interactions and should generally be avoided in pregnant patients. Individuals of childbearing potential need to utilize highly effective contraception for the duration of and up to four days after treatment.
No head-to-head trials of these therapies exist. Below is a comparative review of the new agents and their efficacy.
Table: Current COVID-19 Outpatient Treatment Options
| Nirmatrelvir/Ritonavir | Sotrovimab | Remdesivir | Molnupiravir | |
| Efficacy (prevention of hospitalization/death) |
Relative Risk reduction (RRR): 88% Absolute risk reduction (ARR): 6.3 % vs. 0.8% |
RRR: 85% ARR: 7% vs. 1% |
RRR: 87% ARR: 5.3 % vs. 0.7% |
RRR: 30% ARR: 9.7 % vs. 6.8% |
| Number needed to treat to prevent one hospitalization or death (NNT) | 19 patients | 17 patients | 22 patients | 35 patients |
|
Duration / Regimen |
5 days oral | 1 IV infusion | 3 days IV infusion | 5 days oral |
|
Drug Interactions |
+++ | + | + | + |
| Renal dose adjustment | Yes | No | No | No |
|
Approved time from symptom onset |
5 days | 10 days | 7 days | 5 days |
Ethan Rausch, PharmD, is the Infectious Diseases Pharmacy Resident at the UNC Medical Center.