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Wait…Now Nirmatrelvir Only Works in Vulnerable Patients?

December 22, 2023

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Written by Laura Murphy

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This was a stratified analysis of patients according to vulnerability to complications from COVID-19; it showed clinical benefit in most extremely vulnerable groups but less benefit for healthier patients, even over age 70.

Antivirals—who needs ‘em?
This was a Canadian observational population-based study which analyzed the rates of mortality and hospitalization in 6,866 adults with varying vulnerability to severe disease from February 2022 to February 2023. Patients in this study belonged to four groups who received priority for COVID-19 vaccination; this included patients with severely impaired immune systems (CEV1), moderately impaired immune systems (CEV2), or non-immunocompromised with other high-risk medical conditions (CEV3). The fourth category (EXEL) included patients who were not extremely vulnerable but did have other higher-risk individuals such as patients older than 70 who were unvaccinated.

Patients who received nirmatrelvir-ritonavir were matched with patients in their vulnerability group who were infected within 1 month of each other. Primary outcome was all-cause mortality or emergency hospitalization from COVID-19 within 28 days.

Compared to controls with no treatment, nirmatrelvir-ritonavir was associated with statistically significant reductions in primary outcome in CEV1 (560 patients, risk difference -2.5%, 95%CI -4.8% to -0.2%) and CEV2 group (2,628 patients, risk difference -1.7%, 95%CI, -2.9% to -0.5%). In the CEV3 group (2,100 patients), RD was -1.3% but not statistically significant (95%CI -2.8% to 0.1%). In the EXEL group, treatment was associated with higher risk of the outcome (RD 1.0%) but findings were not statistically significant.

The authors conclude that nirmatrelvir-ritonavir reduced risk of the composite outcome in severely and moderately immunocompromised patients. However, lower-risk individuals (including patients over 70 who were not significantly immunocompromised) did not appear to benefit from treatment. This study shows the effect of nirmatrelvir-ritonavir may be less than originally demonstrated in the EPIC-HR (see here) study, which is similar to other observational studies. However, the predominant circulating variant during this study period was omicron, which was less severe than the delta variant (which was prevalent during the EPIC-HR study), which may account for some results and limit generalizability to other variants.

How will this change my practice?
This stratified analysis of treatment effect based on vulnerability to complications from COVID-19 helps to more thoroughly understand which individuals are likely to benefit from treatment. While I will continue to recommend nirmatrelvir-ritonavir to high-risk patients (particularly immunocompromised patients) based on associated comorbidities, I will not routinely recommend treatment to otherwise healthy patients based on age alone.  However, this may change if more virulent strains emerge.

Editor’s note: This study seems less favorable toward antivirals for COVID-19 than two recent articles. The one in JAMA Network Open showed an association with a marked reduction in hospitalization and mortality and antiviral treatment. The post yesterday showed a similar improvement even in younger patients with comorbidities. This study found improvement with antivirals in the most vulnerable. It is much smaller than the first JAMA study mentioned above: ~6,900 patients vs ~69,000, used a 28-day composite outcome vs 90-day mortality, and had vaccination rates ~90% in the most vulnerable vs ~75% in the prior study. Similar to yesterday’s post, patients with comorbid conditions seem to benefit the most from antivirals. My practice is to follow NIH Treatment guidelines and use an antiviral in patients at high risk of progression of COVID-19. See the end of this post for 5 easy steps to prescribe a COVID antiviral. ~Clay Smith

Nirmatrelvir-Ritonavir and COVID-19 Mortality and Hospitalization Among Patients With Vulnerability to COVID-19 Complications. JAMA Netw Open. 2023 Oct 2;6(10):e2336678. doi: 10.1001/jamanetworkopen.2023.36678.

What are your thoughts?