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Paxlovid (Nirmatrelvir and Ritonavir) by Pfizer – A Game-changer in the COVID-19 Treatment Landscape?

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As we progress into 2022, the world continues its battle against COVID-19, with yet another new strain – Omicron, that emerged towards the end of last year. At present, Singapore is in the midst of an Omicron wave with an average of about 11 000 cases per day. Despite the large numbers, due to the country’s high vaccination rate, majority of the infected individuals either displayed minor symptoms, or were asymptomatic. Only 1491 cases were hospitalized at the time of writing. Patients requiring ICU care or oxygen supplementation in the previous month were also low at 0.04% and 0.3% respectively, while the overall mortality rate maintained at 0.1%.

Although the local situation appears stable now, the growing number of infections warrant a need for safer and more effective COVID-19 treatment alternatives to protect the population; in particular, those of advanced age, who make up a bulk of the more serious cases and fatalities, as well as the immunocompromised and those ineligible for vaccination.

There is also concern that the increasing number of infections could potentially put a strain on the healthcare system. With more therapeutic options available, they can be used to combat the virus, preventing progression to more severe disease states (including hospitalisations and mortality), reducing the time to clinical recovery and minimizing transmission. This article will focus on one of the latest additions to the COVID-19 treatment line-up in the local scene – Paxlovid

About Paxlovid

On 31st January 2022, Singapore’s Health Sciences Authority (HSA), granted interim authorisation under the Pandemic Special Access Route (PSAR) to the nation’s first approved oral medication – Paxlovid, for the treatment of COVID-19 infection in adult patients. 

Paxlovid, developed by Pfizer, is a combination of two kinds of anti-virals, nirmatrelvir and ritonavir, co-packaged together for administration.

How Paxlovid Works

Nirmatrelvir is responsible for the anti-viral effect against the SARS-CoV-2 virus. It is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro) that prevents the virus from processing polyprotein precursors, thereby disrupting viral replication. 

Ritonavir is an HIV-1 protease inhibitor and CYP3A inhibitor. Although it has no activity against the SARS-CoV-2 virus, its ability to block CYP3A-mediated nirmatrelvir metabolism, results in increased serum concentrations of nirmatrelvir. This helps to maintain blood levels of nirmatrelvir for enhanced anti-viral efficacy. 

Recommended Indication of Paxlovid

Paxlovid is endorsed by the HSA for the treatment of mild to moderate COVID-19 infection in adult patients, 18 years old and above, who are at high risk of progression to severe disease, so as to reduce associated hospitalisations and deaths.

Below are risk factors included in the clinical trial:

  • Age 60 years and above, 
  • BMI >25 kg/m2
  • Cigarette smoker
  • Chronic kidney disease
  • Chronic lung disease (including asthma)
  • Cardiovascular disease (including hypertension) 
  • Diabetes
  • Immunosuppression 
  • Sickle cell disease
  • Neurodevelopmental disorders 
  • Other conditions that confer medical complexity (e.g., genetic or metabolic syndromes and certain congenital anomalies)
  • Active cancer
  • Medical-related technological dependence [e.g., continuous positive airway pressure (CPAP)]

Paxlovid is not recommended for use under the following circumstances:

  • Patients with critical COVID-19 infection requiring hospitalisation
  • Prevention of COVID-19 infection
  • Treatment duration greater than 5 days

Dosing and Administration of Paxlovid

Paxlovid should be initiated promptly following a confirmed diagnosis in eligible patients, within 5 days of symptom onset. Both nirmatrelvir and ritonavir tablets must be taken together.

Normal dosing regimen:

  • Nirmatrelvir 300mg (2 x 150mg tablets) + Ritonavir 100mg (1 x 100mg tablet), two times per day for 5 days. 

Dosage adjustments:

  • For patients with moderate kidney impairment (eGFR ≥30 to <60 mL/min), the usual dose of nirmatrelvir should be halved. 
  • Paxlovid is also not recommended in patients with severe renal (eGFR < 30mL/min) or hepatic (Child-Pugh Class C) impairment. 

Contraindications to administration

  • Patients allergic to any of the components. 
  • Drugs cleared primarily by CYP3A that have potentially serious/life-threatening effects associated with elevated concentrations in the body
  • Strong inducers of CYP3A that may significantly lower serum levels of nirmatrelvir/ritonavir, diminishing the viral efficacy of Paxlovid and breeding resistance.  

Efficacy and Safety of Paxlovid

Evidence for the use of Paxlovid is based on clinical results from phase II/III of an ongoing randomized, double-blind, placebo-controlled clinical trial – EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients). 

The study investigates the safety and effectiveness of Paxlovid in adults with COVID-19 infection, not requiring hospitalizations, who are at greater risk of developing severe disease.  

2246 unvaccinated adult participants were recruited into the study, of which 1120 were assigned to the treatment arm, while 1126 received placebo. All subjects were at least 18 years old, and were enrolled within 5 days of their diagnosis, and symptom onset. They also possessed at least one risk factor that increased their likelihood of getting seriously ill from the infection. 

Efficacy

Results from the study demonstrated that treatment with Paxlovid reduced the risk of COVID-19 related hospitalisation or death from any cause at 28 days in comparison to placebo by 88.9% and 87.8% when given within 3 days and 5 days of symptom onset respectively. Both findings were also found to be statistically significant (P<0.001). In addition, no deaths occurred in the Paxlovid arm, while the placebo group recorded 13 fatalities. 

Additional decrease in the SARS-CoV-2 viral load was also observed in the treatment group in contrast to placebo. 

In-vitro data also showed that Paxlovid is active against prevailing variants of concern, including Delta and Omicron. 

Safety

Based on safety data derived from the study, Paxlovid appears to be well-tolerated with a low incidence of serious adverse events. 

An altered sense of taste, diarrhoea, vomiting, hypertension, myalgia, and chills were among the more common adverse events cited.

However, Paxlovid’s potential for clinically significant drug interactions, especially with medications that can interfere with CYP3A activity, must be carefully considered during prescribing. 

Current evidence from the EPIC-HR trial appears to be in favour of the use of Paxlovid, but it must be highlighted that the study’s participants were all unvaccinated. In Singapore’s context, where majority of the population have been immunized, caution should be exercised when extrapolating results to the local population. Although, there is a similar separate ongoing trial EPIC-SR (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients) which involves vaccinated, high risk individuals to look out for. 

Paxlovid Outside Singapore

Beyond our shores, the United States Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for Pfizer’s Paxlovid in December last year. Notably, the FDA’s recommendation differs from that of the HSA, by extending the prescription of Paxlovid to paediatric patients 12 years and older with a weight of at least 40kg. 

Moving Forward with Paxlovid

In conclusion, present clinical results certainly demonstrate the favourable benefit-risk profile of Paxlovid, as a less invasive form of treatment compared to sotrovimab, and casirivimab and imdevimab, that can be prescribed in an outpatient setting for COVID-19 for suitable individuals.

Furthermore, with majority of the population vaccinated and experiencing only mild illness, it will be useful if Paxlovid can prevent progression of mild cases into more severe conditions, which will be beneficial not only to the patient, but also in conserving healthcare resources.  

Even so, Paxlovid is still new, and clinical data is limited. Monitoring of its safety and efficacy needs to be continued as it is introduced into the local scene, and as the EPIC-HR trial wraps up its findings. Not forgetting, the EPIC-SR trial which will provide more insights into treatment in the immunized, as well as the oral drug – Molnupiravir that might join the line-up of oral COVID-19 treatment in Singapore in the near future. 

In the meantime, it is up to clinicians to consider the advantages of Paxlovid against other COVID-19 therapies for use in their patients.

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