Publication date: Jul 16, 2026
Long-term symptoms are common after acute COVID-19, particularly fatigue, cognitive problems, and dyspnoea. Cohort studies have suggested that antiviral treatment of acute COVID-19 might prevent development of post-COVID-19 condition (also known as long COVID), but the efficacy of antivirals has yet to be verified in prospective studies. We aimed to investigate whether treatment of acute SARS-CoV-2 infection with nirmatrelvir-ritonavir would reduce the risk of long COVID. In this double-blind, randomised, placebo-controlled trial, participants were recruited from the municipal health-care service at three sites in Norway (Bergen, Oslo, and Alesund). Non-hospitalised adults aged 18-65 years with SARS-CoV-2 infection confirmed by PCR or lateral flow test and symptoms for 5 days or fewer were eligible for inclusion. Key exclusion criteria included pregnancy or lactation, chronic renal impairment or chronic liver dysfunction, and any person judged by the investigator to need nirmatrelvir-ritonavir treatment due to increased risk of hospitalisation or death. Participants were allocated in a 1:1 ratio to receive oral 300 mg nirmatrelvir and 100 mg ritonavir, or placebo, twice a day for 5 days using a pre-generated randomisation list without stratification or block adjustment. Participants, clinicians, and the study team were masked to treatment allocation. The primary outcome was long COVID, defined as patient-reported fatigue, dyspnoea, and/or cognitive symptoms at 3 months’ follow-up. Safety was analysed as a secondary outcome, and included adverse events, hospital admissions, and deaths. Both the primary outcome and safety were assessed in the intention-to-treat population. The trial is registered with ClinicalTrials. gov (NCT05852873) and is now closed to new participants. Between May 12, 2023, and June 11, 2025, we enrolled 144 participants, of whom 66 were assigned to nirmatrelvir-ritonavir and 78 to placebo. In the protocol we planned to enrol 2000 participants, but the trial was stopped prematurely by the steering committee due to insufficient recruitment. Among the 143 participants who completed follow-up, the risk of long COVID at 3 months was significantly reduced in the nirmatrelvir-ritonavir group (17 [26%] of 66) compared with the placebo group (33 [43%] of 77), corresponding to a relative risk after imputation of data for the single missing value in the placebo group of 0.60 (95% CI 0.37-0.98; p=0.039). In the nirmatrelvir-ritonavir group, five patients discontinued treatment due to adverse events. The most common adverse events in the nirmatrelvir-ritonavir group were change in taste or smell (57 [86%] of 66 in the nirmatrelvir-ritonavir group vs 14 [18%] of 78 in the placebo group) and nausea or vomiting (19 [29%] vs eight [10%]). Inversely, palpitations were more common in the placebo group (ten [13%] of 78) than in the nirmatrelvir-ritonavir group (two [3%] of 66). No severe adverse events were reported. Treatment with nirmatrelvir-ritonavir for acute COVID-19 was associated with a significant reduction in the risk of long COVID at 3 months’ follow-up. The limited sample size precludes firm conclusions, and further clinical trials are warranted. National Health Authorities’ KlinBeForsk programme, Western Norway Regional Health Authority, Helse McF8re og Romsdal Hospital Trust, and The Influenza Centre, Haukeland University Hospital and University of Bergen, Bergen, Norway.
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| Concepts | Keywords |
|---|---|
| Acute | |
| Adverse | |
| Covid | |
| Events | |
| Group | |
| Long | |
| Nirmatrelvir | |
| Norway | |
| Participants | |
| Placebo | |
| Risk | |
| Ritonavir | |
| Symptoms | |
| Treatment | |
| Trial |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | COVID-19 |
| disease | MESH | long COVID |
| disease | MESH | fatigue |
| pathway | REACTOME | SARS-CoV-2 Infection |
| drug | DRUGBANK | Ritonavir |
| disease | MESH | included |
| disease | MESH | liver dysfunction |
| disease | MESH | death |
| disease | MESH | cognitive symptoms |
| disease | MESH | nausea |
| disease | MESH | vomiting |
| drug | DRUGBANK | Pentaerythritol tetranitrate |
| disease | MESH | Influenza |