Paxlovid: Canadian COVID Care Alliance (CCCA)
In January 2022, Health Canada approved the use of the oral antiviral medication called PAXLOVID™. PAXLOVID™ is made of a combination of two medications: nirmatrelvir and ritonavir. PAXLOVID™ is the first oral medication authorized for outpatient use for those who have a positive result from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral test for the treatment of mild to moderate infection. PAXLOVID™ must be taken within five days of symptom onset. Currently in Canada, it is only recommended for patients who are at high risk of progressing to serious COVID-19 disease, including hospitalization or death.
How does PAXLOVID™ work?
PAXLOVID™ is made of a combination of two medications that work together to reduce or stop the replication of SARS-CoV-2. In order for a virus to make more copies of itself inside our cells, it needs to use several tools. One of these tools is an enzyme called SARS-CoV-2 3CL-like protease. This protease is an enzyme that cuts the virus’ protein into smaller parts and is necessary for the virus to make new copies of itself. Nirmatrelvir blocks viral replication by inhibiting SARS-CoV-2 3CL-like protease. Nirmatrelvir has been studied in combination with ritonavir. Ritonavir increases the effectiveness of nirmatrelvir by slowing its breakdown so it is able to work for a longer period of time.
As with any medication, there are a number of key questions that healthcare practitioners can and do use to help determine if it is a good choice for their patients. We felt it important to offer the public the same kind of review, especially since this is a new medication.
When considering treatment of COVID-19, the overarching question is: What factors would a healthcare provider use to determine if a particular COVID-19 therapy is best for a patient? In order to know this, we need to answer a number of targeted questions about the medication itself.
Q1. Does it make people feel better by reducing symptoms?
Q2. Has it shown to prevent progression to severe disease so that hospitalization is not required?
Q3. Does it prevent transmission of SARS-CoV-2 making one less contagious?
Q4. Does it prevent and/or treat Long COVID?
Q5. Is it affordable and readily available?
Q6. It is easy to take (route, duration) with no, or limited drug/food interactions?
Q7. Could it cause harm?
Q8. What actual benefits have been shown from taking it?
Q9. How does it compare to other similar medications?
Q1. Does PAXLOVID™ make people feel better by reducing symptoms?
Answer: At this point, we don’t actually know. The available research has not reported that PAXLOVID™ provided any improvement in symptoms. In one major study (EPIC-HR,2021 NEJM), symptomatic improvement was measured but not reported.
OralNirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19 | NEJM
“Interim analyses of the EPIC-SR (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients) Phase 2/3 study, which included unvaccinated adults who were at standard risk (i.e., low risk of hospitalization or death) as well as vaccinated adults who had one or more risk factors for progressing to severe illness, showed that the novel primary endpoint of self-reported sustained alleviation of all symptoms for four consecutive days as compared to placebo, was not met.”
Q2. Does PAXLOVID™ prevent progression to severe disease so that hospitalization is not required?
Answer: In the EPIC-HR study, PAXLOVID™ appeared to dramatically lower the combined outcome of COVID-19 related hospitalizations or death from any cause compared to the placebo group when expressed as a relative risk reduction of 88.9%; these results are less dramatic when they are expressed as an absolute risk reduction of 5.81%. For a comparison of relative and absolute risk, see - Relative vs Absolute Risk Reduction – Canadian Covid Care Alliance
When clinicians evaluate the benefit of a therapy for their patients, they want to know, did the participants in the therapy’s trial represent the group they want to treat? Currently, PAXLOVID™ is approved for high-risk patients. However, in the EPIC-HR study, most of the participants were not at high risk of developing severe illness.
High risk patients are the ones where treatment would be most beneficial. For example, we know that people over 70 years of age are at the highest risk for severe illness. However, most participants in the study were younger than 65 years old. Only 13% were over 65 and only 3% were over 75 years of age. The trial looked only at unvaccinated patients. Only about 20% of patients had more than one comorbidity and <1% were immunocompromised. Most participants were not using multiple medications, which is usually the case for high-risk patients. In conclusion, the study did not adequately evaluate PAXLOVID™ as treatment for high-risk patients.
In their February 2022 document, the Ontario Science Table raised this concern about patient selection, stating that, “young age and lack of details on concomitant medication use limit study generalizability. Also, the impact of nirmatrelvir/ritonavir on the use of invasive mechanical ventilation was not described.”
Even the Ontario Science Table questions if the study participants represent the type of patient for which PAXLOVID™ is intended.
In the findings section of the summary of the above document, the following needs to be considered:
“Patients who received nirmatrelvir/ritonavir had fewer serious adverse events and adverse events overall than those who received placebo – though the low proportion of enrolled patients ≥ 60 years of age may bias these conclusions. There are many known drug-drug interactions, particularly with ritonavir, and the inclusion criteria of the study may not be reflective of those who may derive the most benefit from this medication in Ontario due to the complexities of prescribing this medication.”
Another study looking at PAXLOVID™, the EPIC-SR study, is ongoing. Both unvaccinated adults who are at standard risk (i.e., low risk of hospitalization or death) as well as vaccinated adults who had one or more risk factors for progressing to severe illness are being enrolled. Results from this ongoing study are unavailable, but a press release reported that there was no appreciable difference between nirmatrelvir/ritonavir and placebo: with 662 subjects enrolled for interim analysis, 2/333 (0.6%) receiving nirmatrelvir/ritonavir and 8/329 (2.4%) receiving placebo were hospitalized.”
The following medical conditions or other factors are considered to place patients at high risk for progression to severe COVID-19 and are recommended for PAXLOVID™ eligibility:
● Older age (i.e., 60 years of age and older)
● Obesity or being overweight (i.e., body mass index [BMI] >25 kg/m2 )
● Current smoker
● Chronic kidney disease
● Diabetes
● Immunosuppressive disease or immunosuppressive treatment
● Cardiovascular disease (including congenital heart disease) or hypertension
● Chronic lung disease (i.e., chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis, and pulmonary hypertension)
● Sickle cell disease
● Neurodevelopmental disorders (i.e., cerebral palsy, Down’s syndrome) or other conditions that confer medical complexity (i.e., genetic or metabolic syndromes and severe congenital anomalies)
● Active cancer
● Medical-related technological dependence not related to COVID-19 (i.e., tracheostomy, gastrostomy, or positive pressure ventilation)
● Other medical conditions or factors (i.e., race or ethnicity) may also place individual patients at high risk for progression to severe COVID-19 and are not limited to the medical conditions or factors listed above.
PAXLOVID™ (nirmatrelvir tablets; ritonavir tablets) | Pfizer Canada (information included in the Canadian Product Monograph)
Q3. Does PAXLOVID™ prevent transmission of SARS-CoV-2 making one less contagious?
Answer: At this point, we don’t actually know.
Unfortunately, prevention of transmission of SARS-CoV-2 was not included in the EPIC-HR study and there was no measurable difference in the viral load. However, recent reports suggest that PAXLOVID™ does not appear to prevent transmission.
Press Release Friday Apr 29, 2022 on PAXLOVID™ failure to prevent infection of household members: Pfizer | CTV News. PAXLOVID™ fails to prevent infection of household members: Pfizer | CTV News
Q4. Does PAXLOVID™ prevent or treat Long Covid?
Answer: We don’t know. There is no evidence to show that PAXLOVID™ prevents or treats Long Covid based on the current study results. This was not included in the primary endpoints of the EPIC-HR or the EPIC-SR studies.
Q5. Is PAXLOVID™ affordable and readily available?
Answer: PAXLOVID™ is publicly funded in Canada and is available for patients that meet the eligibility requirements.
Across Canada, community pharmacies are able to dispense PAXLOVID™ with a prescription provided by a licensed prescribing physician or nurse practitioner for eligible patients. Pharmacists in some provinces including Quebec, Newfoundland and Labrador are able to assess for, prescribe and dispense PAXLOVID™.Q6. Is PAXLOVID™ easy to take (route, duration) with no, or limited drug/food interactions?
Drug-drug interactions leading to potentially serious and/or life-threatening reactions are possible due to the effects of ritonavir on the liver metabolism of certain drugs. Many drugs are processed and broken down in our liver. Ritonavir affects how our liver handles other medications and this may lead to dangerous levels of the medications or their by-products. Contraindications and interactions must be carefully considered before PAXLOVID™ is prescribed or dispensed.
The buzz around PAXLOVID™ has largely obscured one major downside of this treatment. Ritonavir can interact dangerously with a slew of commonly used medications, pumping up the potency of blood thinners, heart-arrhythmia therapies, epilepsy drugs and others. And the patients targeted for its use – those most at risk of serious COVID disease because of age and other health issues – are also the people most likely to be taking those “contraindicated” medications.
In some cases, the interactions could be managed, but it’s clear the problem will limit the pool of potential recipients, experts say. “It has a utility, it has a use,” said Dr. Gerald Evans, head of the Infectious Diseases Division of the Queen’s University medical school. “(But) I certainly would not call it a game-changer.” “A patient on blood thinners could end up with spontaneous bleeding in the gastrointestinal tract or brain”, noted Evans.
“Someone taking pills for hypertension might see their blood pressure fall so much they pass out”, said Dr. Andrew Hill, a pharmacology researcher at the U.K.’s Liverpool University. “There are all kinds of ways that PAXLOVID™ could cause serious harm,” he said.
Ritonavir is also used in HIV treatments, so there is a wealth of knowledge about those potential drug interactions. The U.S. Food and Drug Administration (FDA) product monograph for PAXLOVID™ lists over 100 drugs that it says should not be taken with the COVID pills, or whose use ought to be carefully monitored. The figure below lists a few of these drugs as well as liver enzymes whose functions are impacted by Ritonavir.
Q7. Could PAXLOVID™ cause harm?
Answer: Although this is a critical question, there isn’t enough information to rule out the risk of harm.
All medications can cause harm; we simply need more information to determine the probability of harm in the various patient groups, such as over 65 years olds. This Canadian Health Professional risk communication from Jan 17, 2022, clearly states that, “Not many people have taken PAXLOVID™. Serious and unexpected side effects may happen. PAXLOVID™ is still being studied, so it is possible that all the side effects are not known at this time.”
Q8. What actual benefits have been shown from taking PAXLOVID™?
Answer: It is unknown if the patients identified in the guidelines as being eligible will actually have any benefit from PAXLOVID™.
The EPIC-HR study did not include enough of the very patients who will most likely be prescribed PAXLOVID™ = vaccinated, elderly with multiple comorbidities. This means there is currently no evidence of benefit for vaccinated patients, since only unvaccinated patients were included in the study.
Finally, recent evidence below suggests a potential of relapse of COVID-19 following treatment with PAXLOVID™. The discussion of the case report concludes with, “the potential for symptomatic rebound of viral load, with or without antiviral treatment, has important implications for clinical management and infection prevention.”
Preprint information – relapse of symptomatic SARS-CoV-2 following early suppression
Q9. How does PAXLOVID™ compare to other similar available medications?
Answer: There is evidence to support the use of inexpensive repurposed medications, like ivermectin, as safer oral antiviral therapies for early treatment of SARS-CoV-2 symptoms.
PAXLOVID™ – How does it work and how does it compare to ivermectin? – Canadian Covid CareAlliance
For an interesting and worthwhile video explaining the differences between PAXLOVID™ and ivermectin, here is a link from November 2021 to Dr. John Campbell’s commentary. https://www.youtube.com/watch?v=ufy2AweXRkc
Here is another video by Dr. John Campbell evaluating the evidence for PAXLOVID™ from May 2022: PAXLOVID™, evidence base? - YouTube
Conclusion
There are too many unanswered questions to confidently determine if PAXLOVID™ is a good choice for COVID-19 treatment for eligible patients.
Make sure to boost your immune resilience through the key pillars of optimal health:
● Nutrition (maintain a healthy diet)
● Sleep
● Exercise (mind-body work)
● Immune-supporting supplements where appropriate (including Vitamin D3, Vitamin C, Selenium, Quercetin, Omega 3 Fatty Acids, Probiotics, Melatonin and Nigella Sativa)
● Exposure to nature and sunlight
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