Covid Treatment with Paxlovid

The fight against Covid got significantly easier on November 5th 2021 when Pfizer announced the successful result of their Phase II/III trial of Paxlovid, a new oral at-home treatment for Covid. When started 3 days from on set of symptoms for individual with high risk of developing severe symptom, hospitalization rate dropped 89% and resulted in no deaths compared to placebo. FDA granted emergency use (EUA) in December 2021. When a person is infected with Covid, a war inside the body erupts. The Covid virus’ goal is to replicate and cause maximum damage to the body where ever it goes, causing inflammation, cell damage and organ damage. The body needs to mount a strong immune response to get rid of these unwelcome invaders. The body has the innate immune system and the adaptive immune system to counter them. A person’s adaptive immunity can create antibodies that’s custom made for the specific variant of the virus and stop the virus from entering the cell. The major problem is activating and producing the antibodies take a long time, in days. For a vaccinated and boosted person, this time is shorter than an unvaccinated person but it still takes time. During that ramp up of antibody production, the virus has the upper hand and go uncontested as it replicates and makes more copies of itself. Now with Paxlovid, the body has a new superpower to fight the virus.

How does Paxlovid work?

The Covid virus’ superpower is its ability to hijack our cell’s machinery to make more copies of itself. Imagine an army that can double its size and then double it size again. Over time, thanks for this exponential growth with this double in size effect, this army gets to be humungous and becomes quite formidable and a force to be reckoned with. What would happen if we take away that replication superpower from the virus? The war with virus still rages but it will be on a much smaller scale. The virus load is not doubling anymore and over time, it should shrink as virus dies, or get killed by our immune response. The size of the problem becomes much more manageable for the body when the virus is not replicating. Paxlovid works by disrupting the virus replication process. To understand how Paxlovid works, let’s review how virus replicate.

Viral Replication

The virus requires a complex chain of events to replicate. First the coronavirus enters the body’s cell through its spike protein binding to our cells’ ACE2 receptor. After unlocking ACE2, the virus’s membrane fuses with our cell’s member and the virus enters the cell. Once inside, the virus releases its mRNA to the cell’s cytoplasm. To the cell, the viral mRNA is indistinguishable from cell’s own mRNA. The viral mRNA reaches a Ribosome already in the cell. The Ribosome is a cellular structure whose main purpose is to translate the RNA into protein chains. It is a protein factory. After attaching to viral mRNA, the Ribosome creates the viral enzymes call Proteases and viral polyproteins encoded in the virus’ mRNA. The polyproteins have the potential to become building blocks for making new virus. For that to materialize, the long protein chains must to be cut or cleave at specific places. Somewhere in the long polyprotein chain is the replicase polypeptide. These are responsible for replicating the virus mRNA. The replicase polypeptide is one of points in the polyprotein that the virus need to cut to release the replicase polypeptide. Cutting the protein chain is the responsibilty of enzymes call Proteases. The one that the virus uses is call CL3-PRO. It was built by the Ribosome from the virus’ mRNA. CL3-PRO will cut at the start of the replicase chain. Once the proteins is cut, the replicase polypeptide is activated and other non structural proteins (NSP) are also freed from the long protein chain. The replicase or RNA-dependent RNA Polymerase (RdRp) is used to make more viral genetic material and smaller RNA fragments. The small fragments then make smaller proteins when they go back to the Ribosome. When enough building block is made, a new virus can be assembled. RdPd also delays the body’s innate immune response by blocking coding gene IRF3 (Interferon Regulatory Factor 3) used for production of interferon. Interferon is a part of the innate immune response and its delay allow the virus to go undetected longer.

Paxlovid inhibits viral replication

Paxlovid consists of two components, nirmatrelvir and ritonavir. Nirmatrelvir is the main protease (Mpro) or 3CL-PRO inhibitor. Ritonavir is a HIV-1 protease inhibitor and CYP3A inhibitor but it is not an active SARS-CoV-2 Mpro inhibitor. It is used to slows the metabolism of nirmatrelvir to keep it active longer ( without increase dosage) in the body. Ritonavir blocks the enzyme CYP3A which breaks down protease inhibitors. Nirmatrelvir stops the virus’s 3CL-PRO protease from working properly by binding to its active site. Once nirmatrelvir binds do 3CL-PRO, it no longer can the polyprotein. The virus is not able to get free the replicase from the polyprotein. Without the replicase, it can’t make clone mRNA. Viral replication comes to complete stop.

Benefits

With viral replication halted, the body is able to clear the virus quicker. Getting the virus out quickly reduces the damage from the virus to the brain, heart, and lungs. The risk to developing complications after Covid is higher the longer the virus remains in the body. Study have shown a person who had symptoms longer than 4 weeks has higher chance of developing long Covid where a person continue to experience one or more Covid symptoms. Some of these long Covid symptom can be debilitating such as reduce concentration and fatigue. More serious affects are higher rate of heart attack a year from infection. Given these risks, the quicker a person can clear the virus, the better the outcome. A person is able to get out of isolation sooner and return to regular activities and lessen duration when a person is contagious.

Paxlovid Rebound

There has been reports of Paxlovid rebound which is when the virus comes back a few days after a person tests negative. A possible reason for rebound is the nirmatrelvir level may not be enough or the course was not long enough. Some virus may have survived the five days. Once a person stopped taking Paxlovid, the virus once again is able to resume replication. Even in rebound cases, Paxlovid reduces a person viral load and give the immune system more time to respond and minimize a person’s risk of developing severe symptoms. FDA has requested Pfizer to study the effect of a longer regime.

Who is eligible

CDC recommends this treatment for the following groups of people who are at risk for severe COVID-19:

Age over 50
Unvaccinated or not up to date on COVID-19 vaccination
Specific medical conditions and behaviors

Known Adverse Effects

According a tweet from Dr Anish K. Jha, more than 4 million people have received Paxlovid and there is minimal side effects.

That's why FDA has authorized for people 50 and older and those at serious risk

And remember, you never think about the benefits of the drug without the harms

And more than 4 million people have gotten Paxlovid in the US

With very little in the way of side effects

9/10
— Ashish K. Jha, MD, MPH (@AshishKJha46) August 26, 2022

The side effects include:

dysgeusia – taste disorder. Food may have metallic taste.
diarrhea
hypertension
myalgia – muscle pain

Development History

The search for an effective antiviral started in 2003 during the first SARS outbreak. When SARs outbreak stopped, work on the idea was put on pause and resumed at the start of Covid-19. Scientists built computer model of the protease and then they designed and synthesized over 600 compounds to look for one that can disrupt protease. Tests were performed on cells in a lab and then animals. Nirmatrelvir is the one candidate that worked in the lab and it progressed to human trials.

Effectiveness on Omicron Variants

The medication does not depend on the Virus spike protein and is effective against Omicron variants. It targets the area of the virus that is not changing as fast.

Paxlovid Kinetics

Nirmatrelvir is eliminated from the body by kidney. Ritonavir is metabolized by liver. Both have a half-life of about 6 hrs and exits the body via urine and feces. Paxlovid is not recommended for patients with several renal or liver disease.

Paxlovid Drug Interactions

Ritonavir inhibits CYP3A. Drugs with dependency for CYP3A clearance will be impacted. Your doctor need to review other medications you are taking before prescribing to ensure safety.