A pair of new studies finds no significant benefit of the antiviral drug nirmatrelvir-ritonavir (Paxlovid) in alleviating the symptoms of adult long-COVID patients or in preventing the development of the condition in adolescents.
Safe but ineffective
As described last week in The Lancet Infectious Diseases, Yale University researchers led a decentralized phase 2 randomized controlled trial comparing Paxlovid with placebo in alleviating long COVID in 100 US adults who had symptoms for at least 12 weeks.
"Previous studies examining the association between antiviral therapy during acute SARS-CoV-2 infection and the prevalence of post-infection symptoms yielded mixed results," the authors noted.
From April 2023 to February 2024, 66 women and 34 men were randomly assigned to receive either Paxlovid (two nirmatrelvir tablets and one ritonavir tablet; 49 patients) or placebo and one ritonavir tablet (51 patients) twice daily for 15 days. Three Paxlovid participants and two in the placebo-ritonavir group withdrew before treatment began and weren't included in the safety evaluation. The average patient age was 42.3 years.
The researchers reviewed electronic medical records and tested blood and saliva specimens, and participants completed electronic diaries on treatment compliance, new or worsening symptoms, medication changes, and unscheduled medical visits throughout the study.
Previous studies examining the association between antiviral therapy during acute SARS-CoV-2 infection and the prevalence of post-infection symptoms yielded mixed results.
The average Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Physical Health Summary Score (PHSS) at baseline was 39.6 in the Paxlovid group and 36.3 in placebo-ritonavir recipients. The adjusted change from baseline to day 28 was 0.45 in Paxlovid recipients and 1.01 in the placebo-ritonavir group (adjusted mean difference –0.55).
No deaths or serious adverse events were documented from baseline to week 6. Drug-related treatment-emergent adverse events were reported in 76% of Paxlovid participants, versus 55% in the placebo-ritonavir group, primarily driven by alterations in or loss of taste (48%). Two Paxlovid recipients and one in the placebo-ritonavir group stopped participation early because of adverse events.
"We got an answer that, though disappointing, at least provides more information for us to continue the effort to try to help relieve suffering among these individuals," co-senior author Harlan Krumholz, MD, of Yale, said in a university news release.
In a related commentary, Carolyn Bramante, MD, MPH, of the University of Minnesota, and Clifford Rosen, MD, of Tufts University, asked whether agent-specific biomarkers should be added to the eligibility criteria for long-COVID treatment trials: "Nirmatrelvir–ritonavir is an effective antiviral against SARS-CoV-2, so we ask: would symptom improvement have been more likely if evidence of the virus had been required for inclusion?"
Less healthcare use, COVID-19 severity in acute phase
For the second study, a non–peer-reviewed target trial emulation published on the preprint server medRxiv, a University of Pennsylvania–led team examined the ability of Paxlovid given within the first 5 days of illness to prevent hospitalization, emergency department (ED) visits, outpatient visits, moderate or severe acute illness, and long COVID in infected, non-hospitalized patients aged 12 to 20 years.
The team analyzed acute and post-acute electronic health record data on 2,923 Paxlovid recipients and 31,947 controls who didn't receive the drug from April 2022 to December 2023 at 29 US medical centers participating in the National Institutes of Health's RECOVER consortium. The median patient age was 16.0 years, 46% were male, and 43.2% were White. Long COVID was defined using a single diagnostic code.
This underscores the necessity for ongoing research to fully understand the potential of nirmatrelvir-ritonavir in managing the long-term consequences of COVID-19 among adolescents.
"Adolescents may exhibit different immune responses and clinical outcomes compared with adults, raising questions about the generalizability of adult trial results although a phase 2/3 clinical trial assessing the safety and efficacy of nirmatrelvir-ritonavir treatment in children 6 to 17 years of age with COVID-19 is currently underway," the study authors wrote.
Absolute COVID-19 rates in the Paxlovid and control groups were 0.58% versus 0.96% for hospitalization, 74.17% versus 82.66% for outpatient visits, 1.81% versus 2.28% for ED visits, 3.08% versus 3.99% for moderate/severe acute illness, and 0.21% versus 0.20% for long COVID.
During acute infection, after adjusting for confounding factors, Paxlovid was tied to a lower risk of all-cause hospitalization (relative risk [RR], 0.48), outpatient visits (RR, 0.86), and moderate to severe acute illness (RR, 0.69).
Paxlovid was also tied to a reduced risk of 7 of 16 conditions, including chest pain (RR, 0.41), fatigue and malaise (RR, 0.49), generalized pain (RR, 0.65), headache (RR, 0.60), mental illness (RR, 0.56), musculoskeletal signs or symptoms (RR, 0.63), and respiratory signs and symptoms (RR, 0.61). No evidence, however, suggested that the drug lowered the risk of long COVID (RR, 0.96).
Vaccinated patients showed significant reductions across all measured healthcare-use outcomes, including moderate to severe acute illness and acute symptoms such as abdominal pain, chest pain, fatigue and malaise, fever and chills, headache, and mental illness.
The researchers said that while Paxlovid significantly reduced healthcare use and illness severity, the drug's ability to prevent long COVID is less certain. "This underscores the necessity for ongoing research to fully understand the potential of nirmatrelvir-ritonavir in managing the long-term consequences of COVID-19 among adolescents," they concluded.
