Episode 67- What options exist for outpatient COVID treatment?

Hello and welcome to Episode 67 of ER-Rx. This week, I wanted to discuss EUAs (emergency use authorizations) and then some outpatient COVID treatment options. Although I don’t personally see these meds used in my site’s Emergency Department or ICUs- and you probably don’t either, I do get a lot of questions about what options are available and who qualifies for these treatments, as well as questions about how effective and safe they are. Where I practice, these agents are typically used in an outpatient or clinic setting, and each organization will have their own protocols for how to get patients on these medications.

So, first of all, what is an EUA? An EUA is an FDA authorization for the emergency use of an unapproved product or the unapproved use of an already approved product. This means that the Secretary of Health and Human Services has to declare a public health emergency that affects the national security or health and security of US citizens. To issue an EUA, the disease being treated must have a risk of causing a serious/ life-threatening condition, and based on all of the available data, it has to be reasonable to believe that the product granted the EUA can be effective in diagnosing, treating, or preventing that serious condition. Also, the known benefits of the product have to outweigh the known risks. There must also be no adequate, approved, available alternative. Let’s talk about two oral antiviral agents that recently received EUA status for the outpatient treatment of COVID.

Merck’s drug, molnupiravir, was granted EUA status on December 23rd, 2021, for the treatment of mild-moderate COVID in patients at high-risk for progression to severe disease. These high-risk conditions can be found in the NEJM study linked in the Show Notes or on the CDC website, but it includes factors like diabetes, chronic lung disease, chronic kidney disease, or cancer. This antiviral agent is given as a 5-day course that has to be started within 5 days of symptom onset in patients who are not hospitalized or on supplemental oxygen. In the study published in the NEJM, the “MOVe-OUT” trial, molnupiravir reduced the risk of death or hospitalization for any cause by about 40%– remember that this is a relative risk reduction. Specifically, patients given placebo had about a 10% risk of death or hospitalization, and those given molnupiravir had about a 7% risk—which is an absolute risk reduction of only 3%. This means that we would have to treat 34 patients to prevent one death or hospitalization (this is the number needed to treat (NNT)).

It’s unclear how much this antiviral is going to be used given its low-ish efficacy. There’s also some concern about the drug’s new mechanism of action compared to other antivirals. Molnupiravir incorporates itself into the virus RNA, creating mutations and reducing SARS-CoV-2’s ability to replicate. They call this new mechanism of action “viral error catastrophe” or “viral lethal mutagenesis” — impressive. Some experts have expressed concern about the potential risks of intentionally creating mutations, which could possibly create more dangerous versions of SARS-CoV-2 – but this is expected to be an extremely low risk. This med is also not recommended in pregnancy given some risk shown in animal studies, nor is it recommended in pediatric patients due to the risk of bone growth and cartilage toxicity. But, lucky for us, we have a second antiviral agent, which seems safer and more effective.

Pfizer’s drug Paxlovid (nirmatrelvir/ ritonavir) was granted EUA status on December 22nd, 2021, again for the treatment of mild-moderate COVID in patients at high-risk of progression to severe disease. Remember that neither molnupiravir nor Paxlovid are used to treat severe COVID in hospitalized patients or as pre/ post-exposure to prevent COVID. Paxlovid was ok’d to be used in adults and, unlike molnupiravir, pediatric patients at least 12 years or older weighing at least 40 kg. This is also a 5-day course given within 5 days of symptom onset in patients who are not hospitalized or on supplemental oxygen.

Let’s talk about the two antivirals that make up Paxlovid. Nirmatrelvir is a SARS-CoV-2 main protease (Mpro, 3CLpro, nsp5 protease) inhibitor, which makes the virus incapable of processing protein precursors and prevents viral replication. As you’ll notice, it doesn’t work by causing mutations in the virus RNA, like molnupiravir does. Paxlovid also contains another familiar antiviral, ritonavir. Ritonavir is an HIV-1 protease inhibitor that isn’t actually active against SARS-CoV-2. It’s only included in the combination as a “pharmacokinetic enhancer.” It inhibits CYP3A, the enzyme that breaks down nirmatrelvir, resulting in increased plasma concentrations of the active nirmatrelvir- fascinating stuff.

There are a few things to keep in mind with Paxlovid. It needs to be dose-adjusted in patients with a GFR < 30 or anyone with Child-Pugh Class C liver disease- since we have no data in these patients. The second issue is potentially severe drug-drug interactions. Remember the addition of ritonavir as a “pharmacokinetic enhancer”? Well unfortunately it’ll “enhance” AKA “significantly increase” the concentrations of a lot of other meds that are also cleared by the CYP3A enzyme. Some drug concentrations can be increased enough to cause real patient harm and are therefore contraindicated when taking Paxlovid. This includes meds like the alpha-1 blocker alfuzosin, antiarrhythmics like amiodarone, antipsychotics like lurasidone or clozapine, and specific statins like lovastatin and simvastatin, and this is just naming a few. But on the flip side, if patients are already taking potent CYP3A inducers, the concentration of the antivirals in Paxlovid can be decreased enough to where Paxlovid may not be effective at all, and these meds are also contraindicated. This includes things like the anticonvulsants carbamazepine and phenytoin and even herbal medications like St. John’s Wort. There is also a long list of medications that can be used but require dose adjustments or monitoring if the patient is started on Paxlovid. Make sure you look at the package insert for the full list whenever starting a patient on Paxlovid.

As I mentioned, the data for Paxlovid is more impressive than molnupiravir. The “EPIC-HR” study was a phase 2/3 randomized, placebo-controlled, double-blind trial in unvaccinated non-hospitalized adults with COVID. This trial enrolled patients who were > 60 years old without regard to comorbidities or patients > 18 years old with at least one risk factor for progression to severe disease- these risk factors are very similar to those mentioned earlier for molnupiravir.

This study ended up with over 1,000 patients in each of the Paxlovid and placebo groups. The mean age was 46 years, half of the patients were male, and 72% were white. In terms of results, death or hospitalization for any cause occurred in 0.8 % of patients taking Paxlovid (8/1039 hospitalized with 0 deaths) vs 6.3% in the placebo group (66/1046 hospitalized with 12 deaths) (p <0.0001, RR -5.62, 95% CI -7.21 - -4.03), significantly reducing the risk of death or hospitalization by 87%-- again, a relative risk reduction, with an absolute risk reduction of 5.5%. This means that 18 patients would need to be treated to prevent one death or hospitalization. In a subgroup analysis of patients > 60 years old, the relative risk reduction was 94% (1.1% vs 16.3%, p<0.0001) with a number needed to treat of only 7. Mortality was 0% in the Paxlovid group vs 1.1% in the placebo group overall. Delta was the variant in 98% of patients, which isn’t the case anymore given the emergence of omicron, but since Paxlovid works by blocking viral replication we expect it to have activity against numerous strains, including omicron. The most common adverse events were changes in taste (6% vs < 1%), diarrhea (3% vs 2%), and myalgia (1% vs < 1%). 2% of patients in the Paxlovid vs 4% of patients in the placebo group stopped the trial due to adverse events. So overall, Paxlovid was very, very safe.

Also available for outpatient treatment are monoclonal antibodies, but these are cumbersome to use because they require infusion or injection in a medical setting. To make matters worse, only one of the monoclonal antibodies, sotrovimab, is expected to be effective against omicron. Oral antivirals, especially Paxlovid, seem to be as effective as the monoclonal antibodies and are more patient-friendly for outpatient use. Another advantage of the oral antivirals is the efficacy that they have against SARS-CoV-2 variants like omicron since they are not directed against the spike protein.

In conclusion, so far two oral antiviral agents have been granted EUA status to help prevent hospitalization or death in high-risk patients with COVID. These agents, especially Paxlovid, have efficacy comparable to that of the monoclonal antibodies with the added benefit of being given orally in an outpatient setting, retained efficacy against new strains such as omicron, and very low risks of adverse events. Remember, none of these agents are meant to be a substitute for vaccination against COVID, which remains the best method for preventing hospitalization and death. Keep in mind that supplies of all of these agents is expected to be limited, with each organization making its own decisions on who to prioritize for treatment based on risk factors and product availability.

As always, thank you so much for your time. I’d like to thank the two listeners who have supported the show using the link to BuyMeACoffee.com in the Show Notes – you know who you are, and your support is much appreciated!