Antiviral associated with 26% reduced risk for long COVID

Key takeaways:

• A new study showed that nirmatrelvir reduced the risk for long COVID and post-acute hospitalization and death.
• A separate study revealed risk factors of long COVID, like older age and being female.

The antiviral nirmatrelvir, which is part of Paxlovid, was linked to a significant reduction in the risk for long COVID and post-acute death in patients with at least one risk factor for severe illness, according to researchers.

Recent research has indicated that nearly 19 million adults in the United States may have long COVID. The condition has had a substantial impact on patients, many of whom have been unable to return to work since their diagnosis. The most common symptoms include headache, fatigue and brain fog, but there are many others that can be tied to long COVID.

Yan Xie, PhD, senior clinical epidemiologist at the Clinical Epidemiology Center of the St. Louis Veterans Affairs (VA) Health Care System, and colleagues wrote in JAMA Internal Medicine that prevention of long COVID is an urgent priority for public health.

“Despite [long COVID] affecting a substantial portion of the patient population, there is no approved medication for the prevention or treatment,” they wrote. “The antiviral nirmatrelvir (in combination with ritonavir, marketed under the name Paxlovid) that has been shown to reduce the risk of progression to severe acute COVID-19 has been suggested as a candidate drug that may reduce the risk of developing [long COVID].”

Nirmatrelvir reduces long COVID, regardless of vaccination status

Xie and colleagues conducted a cohort study to assess whether treatment with nirmatrelvir in the acute phase of COVID-19 reduces the risk for long COVID.

To do so, they searched the health care databases of the United States Department of VA to identify patients who had received a positive SARS-CoV-2 test result between Jan. 3, 2022, and Dec. 31, 2022, and met the following criteria: had at least one risk factor for progression to a severe illness, had survived the first 30 days after diagnosis and were not hospitalized on the day of the positive test.

The study included 35,717 patients who were prescribed oral nirmatrelvir within 5 days after a positive test (nirmatrelvir group) and 246,076 patients who did not receive outpatient treatment for COVID-19 within 30 days after a positive test (control group).

Xie and colleagues found that, regardless of vaccination status and history of prior infection, nirmatrelvir treatment within 5 days of a positive SARS-CoV-2 test result was linked to a reduced risk for long COVID across the risk spectrum. These findings, they wrote, “suggest that the salutary benefit of nirmatrelvir may extend to the post-acute phase of COVID-19.”

More specifically, compared with the control group, nirmatrelvir was associated with a 26% reduced risk for long COVID (RR = 0.74; 95% CI, 0.72-0.77) in people who were vaccinated, boosted and in people with primary SARS-CoV-2 infection and reinfection.

This included a reduced risk for 10 of 13 post-acute sequelae:

• acute kidney disease;
• deep vein thrombosis;
• dysautonomia;
• dysrhythmia;
• fatigue and malaise;
• ischemic heart disease;
• muscle pain;
• neurocognitive impairment;
• pulmonary embolism; and
• shortness of breath.

“The present results suggested risk reduction for some but not all the prespecified post–acute sequelae in this analysis,” the researchers wrote. “It is possible that various sequelae are mediated by various mechanisms including some that may be affected by the receipt of antivirals and others that may not.”

Nirmatrelvir was also associated with a 24% lower risk for post-acute hospitalization at 180 days (HR = 0.76; 95% CI, 0.73-0.8) and a 47% lower risk for post-acute death (HR = 0.53; 95% CI, 0.46-0.61), the researchers noted.

“Altogether, the findings suggest that treatment with nirmatrelvir during the acute phase reduces the risk of post-acute adverse health outcomes,” Xie and colleagues wrote. “The totality of evidence suggests that improving the uptake and use of nirmatrelvir in the acute phase as a means of not only preventing progression to severe acute disease but also reducing the risk of post-acute adverse health outcomes may be beneficial.”

Risk factors associated with long COVID

A systematic review and meta-analysis simultaneously published in JAMA Internal Medicine revealed that vaccination helped protect against developing long COVID sequelae but factors such as severe COVID-19, comorbidities and some demographic characteristics like sex and age were connected with an increased risk for the syndrome.

“Not only is it important to recognize which individuals may be at high risk of developing [long COVID] and to offer follow-up care; it is imperative to plan population-level public health measures,” Vasiliki Tsampasian, MD, MSc, a cardiology specialist registrar at Health Education England, and colleagues wrote.

After evaluating 41 articles with a total of 860,783 patients, the researchers found that age (OR = 1.21; 95% CI, 1.11-1.33), high BMI (OR = 1.15; 95% CI, 1.08-1.23), being female (OR = 1.56; 95% CI, 1.41-1.73) and smoking (OR = 1.1; 95% CI, 1.07-1.13) were all associated with a higher risk for developing long COVID.

Additionally, previous hospitalization or ICU admission (OR = 2.37; 95% CI, 2.18-2.56) and the presence of comorbidities such as anxiety, asthma, COPD, depression, diabetes, IHD and immunosuppression (OR = 2.48; 95% CI, 1.97-3.13) were found to be linked to a higher risk for long COVID.

Notably, patients who had been vaccinated with two doses against COVID-19 had a significantly lower risk for developing long COVID than those who were unvaccinated (OR = 0.57; 95% CI, 0.43-0.76). The researchers added that new evidence suggests that vaccination reduces the risk for long COVID and its sequelae “even in individuals with other risk factors, such as older age or high BMI, expanding the benefits of vaccination beyond the morbidity and mortality benefits seen during the acute COVID-19 phase.”

“Given these results, a holistic approach and integrated care pathways may enable suitable support for patients who develop (long COVID) and may allow physicians to be better prepared to care for patients at high risk of developing [long COVID],” Tsampasian and colleagues concluded. “Moreover, in addition to preventing and diminishing the acute phase of the infection, COVID-19 vaccination may protect against [long COVID], giving vaccination additional evidence of benefit.”

‘Until we have better data...’

In a related editor’s note, Mitchell H. Katz, MD, president and CEO of New York City Health and Hospitals, wrote that, in light of the findings from both articles, “it is possible that some of the effect of nirmatrelvir on preventing [long COVID] is by preventing serious sequelae during the initial infection.”

“Until we have better data, the available evidence suggests that nirmatrelvir may prevent [long COVID],” Katz wrote.

References:

• Katz MH, et al. JAMA Intern Med. 2023;doi:10.1001/jamainternmed.2023.0760
• Tsampasian V, et al. JAMA Intern Med. 2023;doi:10.1001/jamainternmed.2023.0750.
• Xie Y, et al. JAMA Intern Med. 2023;doi:10.1001/jamainternmed.2023.0743.