Oral Antivirals for COVID-19: Supply and Demand

In December, the FDA granted Emergency Use Authorizations (EUAs) to 2 oral antiviral drugs for treatment of mild to moderate COVID-19 in outpatients at high risk of progressing to severe disease, including hospitalization or death. The long list of conditions that qualifies infected patients for a prescription for one of these agents includes age >65 years, BMI >25 kg/m2, hypertension, cardiovascular disease, and many others. The Medical Letter reviewed both Paxlovid (Pfizer) and molnupiravir (Merck/Ridgeback) in the January 24, 2022 issue.

Paxlovid, which is a combination of the antiviral nirmatrelvir and the HIV-1 protease inhibitor ritonavir, was clearly the more impressive of the two. In a clinical trial in 2246 eligible patients with symptom onset within 5 days of randomization who were treated with the drug twice daily for 5 days, the incidence of hospitalization or death was 0.8% in the treated patients and 6.3% with placebo, an 88% reduction. There were 12 deaths in the placebo group and none among the patients who received the active drug. Paxlovid has some drawbacks. It cannot be used in patients with severe renal or hepatic impairment, and ritonavir is a strong CYP3A4 inhibitor, which could increase serum concentrations, possibly to toxic levels, of other CYP3A4-substrate drugs that a patient happens to be taking.

Molnupiravir, which still does not have a brand name in the US, was also effective in a similar randomized trial, but less so. It decreased hospitalization or death by 30% compared to placebo (6.8% vs 9.7%), and there were 9 deaths in the placebo group compared to 1 among the molnupiravir-treated patients. As in the Paxlovid trial, most of the patients were infected with the Delta variant. Molnupiravir has a possibly worrisome mechanism of action, targeting viral RNA polymerase by inducing mutagenesis. It is not recommended for use during pregnancy or in patients <18 years old. Unlike Paxlovid, molnupiravir can be used in patients with severe renal or hepatic impairment.

So, of course, we would all prefer to prescribe Paxlovid for our COVID-19 patients who meet the FDA’s specifications. But there is a problem. An article published February 11th in Pharmaceutical Technology tells the story in its title: Molnupiravir supplies dominate in times of Paxlovid scarcity. The article goes on to document the discrepancies, which vary from state to state. At the time of publication, Vermont had a 11-to-1 ratio of molnupiravir to Paxlovid. The ratio was 10-to-1 in Georgia and 8.8-to-1 in Texas. Utah had 20 times as much molnupiravir as Paxlovid. The US government has committed to buying 20 million courses of Paxlovid, but in early February, according to Pharmaceutical Technology, only 364,000 courses had been supplied to providers. An Associated Press online article dated March 2 quoted a government source as promising that the government would have 1 million courses of Paxlovid available this month, with expectations of double that amount in April.

The difference between a 30% and 88% reduction in hospitalization or death sounds enormous, but the difference between 12 deaths versus none and 9 deaths versus 1 does not. If molnupiravir became available in a pharmacy in my town, and Paxlovid did not, I would not hesitate to prescribe molnupiravir for patients who test positive for COVID-19 and are at high risk for severe disease.

Current NIH guidelines recommend 5 antiviral treatments for high-risk outpatients with mild to moderate COVID-19. In order of preference, they are: a 5-day course of oral Paxlovid; a single IV infusion of the monoclonal antibody sotrovimab; or a 3-day course of IV remdesivir (Veklury). If all three of these are inappropriate or unavailable, either a single IV injection of the monoclonal antibody bebtelovimab or a 5-day course of oral molnupiravir is recommended. A chart in The Medical Letter’s free COVID-19 Resources (Treatment of COVID-19 in High-Risk Outpatients) provides additional details about all of these treatments.

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