In a recent study published in JAMA Network Open, researchers examined the prevalence of contraindications to nirmatrelvir-ritonavir (Paxlovid) in hospitalized coronavirus disease 2019 (COVID-19) patients.

Background

The United States Food and Drug Administration (US-FDA) has enlisted several medical contraindications to nirmatrelvir-ritonavir. A recent study suggested that these might be more prevalent in COVID-19 patients at high risk for progression to severe disease.

Clinical trials have shown that Paxlovid treatment reduces the risk of hospitalization and death in most high-risk patients because of its high efficacy versus placebo. Also, it is preferred because it offers the convenience of oral dosing.

However, in certain circumstances, Paxlovid should be avoided due to the effects of ritonavir. In some patients, ritonavir elevates the concentrations of drugs more dependent on cytochrome P450, family 3, and subfamily A (CYP3A) (CYP3A) metabolism, for instance, in patients with severe kidney and liver impairments.

About the study

In the present study, researchers enrolled a large cohort of patients (63,656 inpatients) with confirmed COVID-19 ascertained by a positive reverse transcription–polymerase chain reaction (RT-PCR) test from 36 Greater Paris University hospitals between January 24, 2020, to November 30, 2021. None of these patients had received Paxlovid treatment.

However, since these patients sought hospital admission due to COVID-19-related complications, the researchers assumed that the contraindications rate would be high in these patients.

The primary study outcome was the number of patients with contraindications to nirmatrelvir-ritonavir. Next, the researchers determined the proportion of individuals who died within 28 days of hospitalization. These patients might have needed another therapy (not Paxlovid) in the ambulatory setting.

Furthermore, the team stratified the study analysis by gender, age (less than or older than 65 years), and comorbidities among these patients.

The study followed Strengthening The Reporting of Observational Studies in Epidemiology (STROBE) guidelines and received approval from the institutional review board (IRB) of the Assistance Publique–Hôpitaux de Paris clinical data warehouse.

Study findings

Only 62,525 COVID-19 inpatients met the study criteria, of which 9136 (14.6%) had a medical contraindication to nirmatrelvir-ritonavir. The study population comprised 31,561 women [50.5%], and the mean age of the participants was 52.8 years. The researchers noted that medical contraindication rates to nirmatrelvir-ritonavir were higher in men than women (18% vs. 11.3%). Likewise, these rates were higher in older patients than young patients (26.9% vs. 8.8%) and people with comorbidities vis-a-vis those with no comorbidities (>37% vs. 3.9%).

Notably, ~50% (2463 of 4861) of patients who died due to COVID-19 also had a contraindication to nirmatrelvir-ritonavir. In these patients, the rates were similar in men and women, older and younger patients, but higher in patients with versus without comorbidities. Particularly, the most prevalent contraindications in the study cohort were severe kidney impairment and the use of medications dependent on the CYP3A gene for clearance.

Conclusions

The current study findings raise concerns that medical contraindications to nirmatrelvir-ritonavir might have confounded the results of observational studies. Such studies might have, thus, overestimated Paxlovid's treatment efficacy, especially if they had not excluded patients with contraindications to this treatment. In fact, some of the contraindicated medications should be put on hold (temporarily) in the context of using Paxlovid.

Nevertheless, in agreement with prior studies, the current study also found medical contradictions to nirmatrelvir-ritonavir in individuals hospitalized with COVID-19.

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.