A 5-day treatment course with nirmatrelvir–ritonavir appears to extend its benefit past the acute infection period, having been linked to reduced long COVID risk in the randomized controlled PANORAMIC Norway trial.
At the 3-month follow-up, 26 percent of patients in the nirmatrelvir–ritonavir group reported long COVID symptoms, including fatigue, dyspnoea, and/or cognitive symptoms, compared with 43 percent of those in the placebo group. [Lancet Infect Dis 2026;doi:10.1016/S1473-3099(26)00244-6]
Treatment with nirmatrelvir–ritonavir was associated with a 40-percent relative reduction in long COVID symptoms at 3 months (relative risk, 0.60, 95 percent confidence interval, 0.37–0.98; p=0.039).
“This is the first placebo-controlled randomized trial to show that treatment with nirmatrelvir–ritonavir for acute COVID-19 could potentially prevent persistent symptoms,” said first author Dr Oddvar Oppegaard from the University of Bergen, Bergen, Norway, and colleagues.
The finding aligns with those reported in several retrospective studies and provides support for a causal relationship between acute COVID-19 and the constellation of persistent long COVID symptoms, Oppegaard and colleagues added. [Prev Med Rep 2025;57:103188; Sci Rep 2023;13:19688; Open Forum Infect Dis 2025;12:ofaf567]
How early treatment works
In an accompanying editorial, Drs J Daniel Kelly and Michael Peluso, both from the University of California San Francisco, California, US, echoed Oppegaard and colleagues. “The [PANORAMIC Norway] trial, in which the intervention directly targeted SARS-CoV-2 during the acute phase, suggests that early viral replication can initiate self-sustaining or persistent harmful biological processes that contribute to long COVID,” they wrote. [Lancet Infect Dis 2026;doi:10.1016/S1473-3099(26)00361-0]
Kelly and Peluso proposed several possible mechanisms linking early antiviral treatment to reduced post-acute sequelae.
“First, acute virological factors—maximum nasal viral load and duration of viral shedding—have been associated with subsequent long COVID and could be attenuated by early treatment. Second, reducing viral replication could alter the early host immune response, limiting immune dysregulation and allowing antiviral immunity to more effectively control the virus,” they said.
“Finally, acute-phase treatment could prevent or reduce postacute processes implicated in long COVID, including SARS-CoV-2 persistence, herpesvirus reactivation, and immune dysfunction,” they added.
Long COVID prevention
The PANORAMIC Norway trial should prompt “a broader long COVID prevention agenda,” according to Kelly and Peluso. They called for more trials to evaluate additional agents and therapeutic approaches, optimize the timing and duration of treatment, and test mechanistically informed combinations designed to interrupt the biological processes that lead to long COVID.
“Showing that altering acute-phase biology can improve postacute biological and clinical outcomes could also inform prevention strategies for other infection-associated chronic conditions, including those arising from future pandemic threats. Such an agenda would represent a paradigm shift in how we approach the relationship between acute infections and chronic disease,” they concluded.
PANORAMIC Norway
PANORAMIC Norway was conducted at three municipal healthcare service sites in Bergen, Oslo, and Ålesund. A total of 144 nonhospitalized adults with confirmed SARS-CoV-2 infection were recruited within 5 days of symptom onset. The trial ended early after failing to meet its enrolment target of 2,000 participants.
The participants were randomly assigned to receive 300-mg nirmatrelvir plus 100-mg ritonavir (n=66; median age 48 years, 68 percent female) or placebo (n=78; median age 49 years, 63 percent female), administered orally twice daily for 5 days.
Most participants (98 percent) were vaccinated against SARS-CoV-2, with two participants in the placebo group and one in the nirmatrelvir–ritonavir group having never received a SARS-CoV-2 vaccine. Three participants had received a single dose, all of whom were in the placebo group.
In terms of safety, the most common adverse events (AEs) in the nirmatrelvir–ritonavir group were change in taste or smell (86 percent vs 18 percent in the placebo group) and nausea or vomiting (29 percent vs 10 percent). On the other hand, palpitations were more frequent in the placebo group than in the nirmatrelvir-ritonavir group (13 percent vs 3 percent).
AEs led to treatment discontinuation in five patients in the nirmatrelvir–ritonavir group. There were no severe AEs documented.