Tomorrow evening, we’re off to California!
Today, I’m going to write a bit about the new Pfizer study published in the New England Journal of Medicine, nirmatrelvir plus ritonavir (Paxlovid) for for high-risk, non-hospitalized adults with COVID.
This was a double-blind, randomized, controlled trial of 2246 patients comparing oral nirmatrelvir plus ritonavir to placebo. The study demonstrated that nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo (relative risk reduction). There were no evident safety concerns with the medication, just mild dysgeusia (a taste disorder) and diarrhea in a small percentage of patients. The study was a slam dunk, right? An oral, small molecule drug that is highly effective against severe COVID!
In an accompanying editorial, Drs. Eric Rubin and Lindsey Baden (my attendings from infectious diseases fellowship at Brigham and Women’s Hospital), discuss the implications of the trial. They remind us that nirmatrelvir is a protease inhibitor, similar to the class of medications used to treat HIV. The ritonavir helps boost the nirmatrelvir levels, just like ritonavir boosts lopinavir (Kaletra), an HIV protease inhibitor.
However, Drs. Rubin and Baden remind about the difference between absolute and relative risk reduction. Although the relative risk reductions were large (89%), those at lower risk had a very small absolute benefit. For example, in those who were SARS-CoV-2 seropositive at baseline, the absolute risk reduction was only about 1 percentage point. Therefore, the greatest absolute benefit is among those at highest risk. You can calculate the number needed to treat from the absolute risk reduction.
Also of importance – the study was performed when Delta was the main circulating variant, so we don’t know how nirmatrelvir might perfom against Omicron or emerging variants. Resistance will also likely be an issue, the editorialists also write.
The antiviral should be given within 5 days after symptom onset (ideally sooner after infection). It should be reserved for patients with the highest risk for disease progression, particularly those with multiple and serious coexisting conditions and those unable to mount sufficient immune responses (on cancer chemotherapy, etc).
Most important are equity and rationing concerns, because supplies are currently quite constrained. Will public health authorities be able to direct Paxlovid to the most marginalized, underserved communities where it is needed the most?
Given the history of vaccine inequity, and the general brokenness of America’s health system, I highly doubt that will be the case. The people with the most resources will get the best treatment. To address our health care crisis, we need a nonprofit single payer / Medicare-for-all. I encourage everyone to join the movement for health and racial justice.
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Philip A. Lederer 
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