Paxlovid vs Molnupiravir vs Ivermectin: What are the Differences?

If you are confused about the recommendations made by different professional groups for the COVID-19 pandemic, you've come to the right place. 

The number of options for the treatment of COVID-19 has increased drastically in recent months, thus making it complicated when it comes to choosing the right combination. In general, there are 3 broad categories of medical interventions:

1. Prevention or Prophylaxis e.g. vaccine
2. Early out-patient treatment
3. Hospital treatment

McCullough et al. Reviews in Cardiovascular Medicine, 2020

All these treatments come with various technologies and jargons, thus could be overwhelming and confusing for you as a layperson. Generally, multiple treatments and strategies are used in combination to achieve the best possible outcome. 

The medical community themselves are battling over repurposed drugs like ivermectin and hydroxychloroquine on whether they should be used to treat and prevent COVID-19. On one side are experts telling you that more research is needed before the treatment can be fully authorized and confirmed. On the other, are experts telling you that the potential benefits outweigh the risk and a 'wait and do nothing' position is not acceptable. Confused? 

How do you deal with different expert groups dishing out conflicting guides? A common issue is that certain groups have pre-defined narrative that they would like to support. Therefore, only studies that support that pre-defined narrative are picked and cited as references. This is what we call as 'cherry-picking'. Cherry picking will naturally lead to a 'biased' and 'manipulated' decision. In order to get the truth out, scientific information needs to be analyzed in a comprehensive, updated and non-biased manner.

In this article, we will do a roundup and cover 3 popular oral anti-viral treatments i.e. Paxlovid, Molnupiravir and Ivermectin.

Contents:

• Paxlovid and COVID-19
• The NIH COVID-19 Treatment Guidelines for High-Risk, Non-hospitalized Patients With Mild to Moderate COVID-19
• Molnupiravir and COVID-19
• Ivermectin and COVID-19
• Ivermectin and FLCCC I-MASK+ Early Treatment Protocol
• Molnupiravir vs Ivermectin
• Paxlovid vs Ivermectin vs Molnupiravir

Paxlovid and COVID-19

U.S. health regulators authorized the first pill against COVID-19 in December 2021 (Associated Press), a Pfizer drug that Americans will be able to take at home to head off the worst effects of the virus.

The long-awaited milestone comes as U.S. cases, hospitalizations and deaths are all rising and health officials warn of a tsunami of new infections from the omicron variant that could overwhelm hospitals.

The drug, Paxlovid (ritonavir-boosted nirmatrelvir), is a faster, cheaper way to treat early COVID-19 infections, though initial supplies will be extremely limited. All of the previously authorised drugs against the disease require an IV (intravenous) or an injection.

Paxlovid is also no. 1 in this drug league table:

“The efficacy is high, the side effects are low and it’s oral. It checks all the boxes,” said Dr. Gregory Poland of the Mayo Clinic. “You’re looking at a 90% decreased risk of hospitalization and death in a high-risk group — that’s stunning.”

The Food and Drug Administration authorized Pfizer’s drug for adults and children ages 12 and older with a positive COVID-19 test and early symptoms who face the highest risks of hospitalization. That includes older people and those with conditions like obesity and heart disease. Children eligible for the drug must weigh at least 88 pounds (40 kilograms).

The pills from both Pfizer and Merck are expected to be effective against omicron because they don’t target the spike protein where most of the variant’s worrisome mutations reside.

Pfizer currently has 180,000 treatment courses available worldwide, with roughly 60,000 to 70,000 allocated to the U.S. Federal health officials are expected to ration early shipments to the hardest hit parts of the country. Pfizer said the small supply is due to the manufacturing time — currently about nine months. The company says it can halve production time next year.

The U.S. government has agreed to purchase enough Paxlovid to treat 10 million people. Pfizer says it’s on track to produce 80 million courses globally next year, under contracts with the U.K., Australia and other nations.

Health experts agree that vaccination remains the best way to protect against COVID-19. But with roughly 40 million American adults still unvaccinated, effective drugs will be critical to blunting the current and future waves of infection.

The U.S. is now reporting more than 140,000 new infections daily and federal officials warn that the omicron variant could send case counts soaring. Omicron has already whipped across the country to become the dominant strain, federal officials confirmed earlier this week.

Against that backdrop, experts warn that Paxlovid’s initial impact could be limited.

For more than a year, biotech-engineered antibody drugs have been the go-to treatments for COVID-19. But they are expensive, hard to produce and require an injection or infusion, typically given at a hospital or clinic. Also, laboratory testing suggests the two leading antibody drugs (from Regeneron and Eli Lilly) used in the U.S. aren’t effective against omicron.

Pfizer’s pill comes with its own challenges.

Patients will need a positive COVID-19 test to get a prescription. And Paxlovid has only proven effective if given within five days of symptoms appearing. With testing supplies stretched, experts worry it may be unrealistic for patients to self-diagnose, get tested, see a physician and pick up a prescription within that narrow window.

“If you go outside that window of time I fully expect the effectiveness of this drug is going to fall,” said Andrew Pekosz, a Johns Hopkins University virologist.

The FDA based its decision on company results from a 2,250-patient trial that showed the pill cut hospitalizations and deaths by 89% when given to people with mild-to-moderate COVID-19 within three days of symptoms. Less than 1% of patients taking the drug were hospitalized and none died at the end of the 30-day study period, compared with 6.5% of patients hospitalized in the group getting a dummy pill, which included nine deaths.

Pfizer’s drug is part of a decades-old family of antiviral drugs known as protease inhibitors, which revolutionized the treatment of HIV and hepatitis C. The drugs block a key enzyme which viruses need to multiply in the human body.

How much will Paxlovid cost? The U.S. will pay about $500 for each course of Pfizer’s treatment, which consists of three pills taken twice a day for five days. Two of the pills are Paxlovid and the third is a different antiviral that helps boost levels of the main drug in the body.

The COVID-19 Treatment Guidelines Panel’s Statement on Therapies for High-Risk, Nonhospitalized Patients With Mild to Moderate COVID-19

The US FDA issued EUAs (January 2022) that allow 2 new oral antiviral agents to be used as treatments for COVID-19 in nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to serious disease: ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir. 

This statement contains the Panel’s recommendations for treating these non-hospitalized patients using the currently available therapies.

The Panel’s recommendations take into account the efficacies of these drugs and the high prevalence of the Omicron VOC. When resources are limited, therapy should be prioritized for patients who are at the highest risk of progressing to severe COVID-19 (see the Panel’s statement on patient prioritization for outpatient therapies).

The Panel’s current outpatient treatment recommendations are as follows (in order of preference):

• Paxlovid (nirmatrelvir 300 mg plus ritonavir 100 mg) orally twice daily for 5 days
• Sotrovimab 500 mg administered as a single intravenous (IV) infusion
• Remdesivir 200 mg IV on Day 1 followed by remdesivir 100 mg IV on Days 2 and 3
• Molnupiravir 800 mg orally twice daily for 5 days

Pfizer pill slashes risk of getting seriously ill (DailyMail)

Trials of Paxlovid, involving an initial 1,219 participants, were stopped early because it worked so well.

Among those who took the drug – which is made by US firm Pfizer – within three days of getting Covid symptoms, less than 1 per cent were admitted to hospital and none died.

Since Paxlovid works by blocking a protease enzyme, should I be concerned about taking digestive enzymes that contain proteases? (ConsumerLab)

No, you should not be concerned. The proteases produced by your body and found in digestive enzyme supplements, which help digest protein in foods, are different from the viral protease (3CL) that is needed by coronaviruses to replicate (Zhang, Science 2020) and is the target of the antiviral protease-inhibitor drug Paxlovid. Taking a supplement that contains proteases to digest food is not likely to affect the course of COVID-19 infection or the activity of antiviral drugs.

Molnupiravir and COVID-19

Associated Press (December 1, 2021) — A panel of U.S. health advisers narrowly backed Molnupiravir from Merck:

“I see this as an incredibly difficult decision with many more questions than answers,” said panel chair Dr. Lindsey Baden of Harvard Medical School, who voted in favor of the drug. He said FDA would have to carefully tailor the drug’s use for patients who stand to benefit most.

The recommendation came after hours of debate about the drug’s modest benefits and potential safety issues. Most experts backing the treatment stressed that it should not be used by anyone who is pregnant and called on FDA to recommend extra precautions before the drug is prescribed, such as pregnancy tests for women of child-bearing age.

Merck said final study results showed molnupiravir reduced hospitalization and death by 30% among adults infected with the coronavirus, when compared with adults taking a placebo. That effect was significantly less than the 50% reduction it first announced based on incomplete results.

For many panelists, the modest effect wasn’t enough to outweigh the drug’s potential toxicity to human fetuses.

“Given the large potential population affected, the risk of widespread effects on potential birth defects has not been adequately studied,” said Dr. Sankar Swaminathan of the University of Utah School of Medicine, who voted against the drug.

FDA scientists told the panelists earlier Tuesday that company studies in rats showed the drug caused birth defects when given at very high doses. FDA staffers concluded the data “suggest that molnupiravir may cause fetal harm when administered to pregnant individuals.”

The agency is weighing a blanket restriction against any use in pregnant women or allowing doctors to use the drug in rare cases. Some panelists said that option should be left open for pregnant mothers who have high-risk COVID-19 and may have few other treatment options.

Dr. Janet Cragan, who backed the drug, said that even with tight restrictions some pregnant women would inevitably take the antiviral.

“I don’t think you can ethically tell a woman with COVID-19 that she can’t have the drug if she’s decided that’s what she needs,” said Cragan, a panel member and staffer with the Centers for Disease Control and Prevention. “I think the final decision has to come down to the individual woman and her provider.”

Merck’s drug uses a novel approach to fight COVID-19: It inserts tiny errors into the coronavirus’ genetic code to stop it from reproducing. That genetic effect has raised concerns that the drug could spur more virulent strains of the virus. FDA regulators said Tuesday that risk is theoretical but many panelists said it should be carefully tracked in follow-up studies.

Antiviral pills have long been seen as a key advance beyond currently used antibody drugs, which must be injected or infused by health professionals. But given the shortcomings of Merck’s data, several experts said they would prioritize patients to receive the older drugs.

Ivermectin and COVID-19

Ivermectin is a well-known, FDA-approved anti-parasite drug that has been used successfully for more than four decades to treat onchocerciasis “river blindness” and other parasitic diseases on humans. It’s been used for decades for this purpose by over 3.7 billion people, and is considered safe and effective. 

Ivermectin has also being researched for it's potential effectiveness for dengue viral infection (Ref, Ref) and even colo-rectal cancer (Ref). Similarly, ivermectin has also been shown to possess antiviral activity against a whole host of other RNA viruses (Zika, yellow fever, human immunodeficiency virus type 1) (Ref).

It has an increasing list of indications due to its antiviral and anti-inflammatory properties, and is included on the WHO’s Model List of Essential Medicines.

Is ivermectin a zinc ionophore? Although there are many articles stating it is but most articles do not provide scientific references to support the claim. We have found studies that showed that ivermectin has a probable ionophore nature: 

• Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action (Naunyn Schmiedebergs Arch Pharmacol. 2020).
• The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug (Am J Cancer Res. 2018)

Ivermectin Peer Reviewed and Other Studies

For a comprehensive review on ivermectin, please refer to the peer-reviewed publication; Review of the Emerging Evidence Supporting the Use of Ivermectin in the Prophylaxis and Treatment of COVID-19 and the included references.

For an up-to-date overview of all published studies on ivermectin in the treatment and prevention of COVID-19 we recommend visiting c19ivermectin.com; in addition, a meta-analysis of all studies can be found at ivmeta.com (constantly updated). For adoption and regulatory status of ivermectin globally, check out "Countries using Ivermectin".

Ivermectin and FLCCC I-MASK+ Early Treatment Protocol

The Front Line COVID-19 Critical Care (FLCCC) Alliance was initially formed as a working group during the early COVID-19 pandemic days in response to multiple early reports of COVID patients with an inexplicably high need for prolonged mechanical ventilation and an excessive death rate.

Based on rapidly emerging clinical trials evidence, the FLCCC team has developed the I-MASK+ protocol for prophylaxis and at home treatment of early stage COVID-19.

For updated early outpatient protocol (COVID-19 positive), please check out FLCCC I-MASK+ protocol.

For post-covid or long covid syndrome, check out FLCCC (Front Line COVID-19 Critical Care Alliance) I-Recover Post-COVID Protocol. For a simplified version of the I-MASK+ protocol, the FLCCC has also developed the I-MASS protocol.

Ivermectin for COVID-19: Real-time meta analysis

Check out the evidence tracking on Ivermectin versus COVID-19 from Ivmmeta.com (constantly updated).

Concerns and Cautions:

• Ivermectin has a number of potentially serious drug-drug interactions. Please check for potential drug interaction at Ivermectin Drug Interactions - Drugs.com. The most important drug interactions occur with cyclosporin, tacrolimus, anti-retroviral drugs, and certain anti-fungal drugs. 
• Ivermectin is also lipophilic and therefore, bioavailability is maximised on a full stomach; or best to be taken with meal.

Related: 

• List of Doctors that will prescribe Ivermectin

• List of Pharmacies that will fill Ivermectin

Ivermectin vs Molnupiravir

Retired nurse lecturer John Campbell, Ph.D., makes a critical comparison of the two in a YouTube video. To be upfront, Campbell says he is pro-vaccine and pro-antiviral.

Ivermectin, he says, is one of the most-studied, repurposed drugs and, it’s not only FDA-approved for humans, but it won a Nobel prize as it “revolutionized the human treatment of a parasitic disease.” It also has demonstrated “broad spectrum antiviral activity against many viruses including HIV, Zika and MERS” and it inhibits the replication of the SARS coronavirus, and in fact got rid of 99.98% of SARS-viable particles in 48 hours.

Like ivermectin, molnupiravir is an oral drug, but it’s converted in the liver, and there is a safety concern that the metabolite action could also be mutagenic — cancerous — in mammalian cells as well as a trigger for birth defects in a fetus. While Merck says that’s not going to be a problem, Campbell says evidence he’s looking at shows “it at least needs looking into” because “if it stops the normal replication of RNA is it going to stop the normal replication of our DNA?”

Ivermectin, on the other hand, binds to the spike protein to stop it from going into your cells. It’s also an anti-inflammatory with high efficacy that inhibits cytokines and has very few side effects reported in its years of usage.

 

Dr John Campbell further reports on a comparative analysis of molnupiravir and ivermectin published in the Austin Journal of Pharmacology and Therapeutics. The advantage molnupiravir has over remdesivir is that it is administered orally and can be used for early treatment in an outpatient setting.

In the video above,  Campbell reviews a paper published in the Austin Journal of Pharmacology and Therapeutics that was a chemical comparison of the pharmacological effects of molnupiravir and ivermectin. Looking at the two ways science uses to develop new treatments when a new condition arises, Campbell explains the first is to create a new drug and the second is to repurpose medications used for other conditions. For example, aspirin originally was used to treat fever. Once it became evident that it was also effective against pain, doctors began recommending it to relieve headaches and other minor aches and pains. Subsequently, it was found that aspirin was an effective antiplatelet, as well, and this function was added to the known uses for aspirin. 

According to the paper, Ivermectin is the "most studied, 'repurposed' medication globally, in randomized clinical trials, retrospective studies and meta-analysis." Ivermectin is an FDA-approved, broad spectrum antiparasitic with known anti-inflammatory properties.

The data in the comparison paper show molnupiravir is more potent in-vitro than ivermectin, which means it needs less drug to work with a lower tissue concentration. The amount of time the maximum drug dose is found in the serum is one to 1.75 hours for molnupiravir and four to six hours for ivermectin.

Interestingly, the half-life for Merck's drug is seven hours and the half-life for ivermectin is 81 to 91 hours. This is the amount of time it takes for your body to reduce the active ingredients in the drug by half. Campbell also reviews the following factors:

Safety — No matter how well a drug works, if it's not safe for use, it cannot be effective. Offering some examples of how ivermectin's safety compares to other drugs, according to Campbell the global database of the World Health Organization, VigiBase, recorded 5,593 adverse events from ivermectin after 3.7 billion doses were administered to humans. 

For comparison, VigiBase recorded 136,222 adverse events for amoxicillin and 165,479 for ibuprofen. At this time there is no VigiBase data available for molnupiravir, so no comparisons can be made for that drug yet. To take the example one step further, an outside look at acetaminophen adverse events shows that this drug (aka Tylenol) is many times more dangerous than ivermectin.

In the U.S. alone the National Institutes of Health's STATPearls manual reports that there are 2,600 hospitalizations, 56,000 emergency room visits and 500 deaths each year for acetaminophen overdoses as of July 2021. And, the drug is the second leading cause of liver transplantation worldwide and the leading cause of transplantation in the U.S.

Efficacy — According to interim data from Merck, molnupiravir reduced hospitalizations or deaths by 50% in 385 participants who had at least one risk factor associated with poor disease outcome. A meta-analysis of 15 trials that included 2,438 participants demonstrated that ivermectin could reduce the risk of death by 62%.

Paxlovid vs Molnupiravir vs Ivermectin

Is Paxlovid like Ivermectin? Clinical evidence to date has reported promising results for Ivermectin in prevention, early treatment as well as late treatment for COVID-19. 

Both Paxlovid and ivermectin are protease inhibitors. However, Pfizer's Paxlovid (Generic Name: Nirmatrelvir / Ritonavir) and Merck's Molnupiravir (UK Brand Name: Lagevrio) have been issued Emergency Use Authorizations (EUAs) by the US FDA for high risk COVID-19 patients whereas ivermectin has not been authorized to be used for COVID-19.

Note: On December 22 and 23, 2021, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) that allow Paxlovid and Molnupiravir to be used in high risk patients.

According to GoodRx Health (Jan 26, 2022): Studies suggest that Paxlovid can lower the risk of severe COVID-19 for high-risk people by almost 90%. Studies suggest molnupiravir can lower this risk by about 30% in high risk people.

According to AP News (Dec 23, 2021): Pfizer’s drug is all but certain to be the preferred option because of its mild side effects and superior effectiveness, including a nearly 90% reduction in hospitalizations and deaths among patients most likely to get severe disease.

Pfizer’s drug is part of a decades-old family of antiviral pills known as protease inhibitors, a standard treatment for HIV and hepatitis C. They work differently than Merck’s pill and haven’t been linked to the kind of mutation concerns raised with Merck’s drug.

According to AP News (Dec 1, 2021): Pfizer said that its drug shouldn’t be affected by the omicron variant’s mutations.Both drugs require patients to take multiple pills, twice a day for five days.The U.S. government has agreed to purchase 10 million treatment courses of Pfizer’s drug, if it’s authorized. That’s more than three times the government’s purchase agreement with Merck for 3.1 million courses of molnupiravir.

Summary 

The important key takeaway is 'early' treatment. As anti-virals, Paxlovid, Molnupiravir and Ivermectin all need to be given early (within five days of symptoms appearing). That said you should never attempt to self medicate without the guidance of a licensed medical provider. If you are not a medical doctor, you are likely to find the above information overwhelming and complicated. The aim of this article is to empower you with a better understanding of the options available and to discuss the options with your medical doctor.

Updates: 

Pfizer's softly, COVID marketing approach continues with COVID-Fighting Pill Ad

Test to Treat initiative - Assistant Secretary for Preparedness and Response (ASPR)