Nearly 15% of COVID-19 patients admitted to 36 Paris University hospitals had contraindications—factors that rule them out, based on recommendations—to the antiviral combination nirmatrelvir-ritonavir (Paxlovid), finds a study published yesterday in JAMA Network Open.
Paxlovid, which can reduce hospitalization and death among high-risk COVID-19 patients, is often the antiviral of choice because of its efficacy and ease of oral dosing, the authors noted.
There are multiple instances, however, in which Paxlovid is not recommended, often because of the effect of ritonavir. Ritonavir may elevate the concentrations of drugs that strongly depend on hepatic cytochrome P-450 3A (CYP3A) metabolism, such as alfuzosin for high blood pressure, amiodarone to correct heart rhythm problems, and cholesterol-lowering statin drugs.
Patients who take drugs heavily dependent on CYP3A clearance can't take Paxlovid because ritonavir can raise the concentrations of those drugs to dangerous levels. Conversely, CYP3A inducers can lead to loss of Paxlovid virologic response by lowering nirmatrelvir levels.
Also, the US Food and Drug Administration (FDA) does not recommend Paxlovid in people with liver or kidney impairment because of a lack of safety data. And the FDA recommends the drug only for people 12 years or older who weigh at least 88 pounds.
Higher contraindication rates in men, seniors
Universite Paris Cite researchers evaluated eligibility for Paxlovid among 62,525 hospitalized COVID-19 patients from Jan 24, 2020, to Nov 30, 2021. Median age was 52.8 years. No patients received Paxlovid.
Of all patients, 14.6% had a contraindication to Paxlovid, and a higher proportion of them were men than women (18.0% vs 11.3%), older than 65 years (26.9% vs 8.8%), and had underlying medical conditions (more than 37.0% for most comorbidities vs 3.9%).
Of 4,861 patients who died within 28 days, 50.7% had a contraindication to Paxlovid, with similar rates by sex and age but elevated rates in patients with chronic illnesses. The most common contraindications were severe kidney impairment and use of drugs metabolized through CYP3A liver clearance. CYP3A is an enzyme responsible for drug metabolism in gastrointestinal and liver tissues.
"Furthermore, patients with severe kidney impairment and severe liver impairment were excluded from the clinical trials," the authors wrote. "These medical contraindications may be prevalent in patients with COVID-19 who are at high risk for progression to severe disease."
The researchers said the results highlight the risk of confounding by contraindication in observational studies of Paxlovid, which may overestimate drug efficacy if patients with contraindications aren't excluded. They also said that some contraindicated drugs could be paused during Paxlovid treatment.
"These findings support the need to anticipate supplies for alternative approved treatments and those that are under regulatory review (eg, SARS-CoV-2 main protease inhibitors), and for continued research on less expensive treatment options for low- and middle-income countries," they concluded.
