Nirmatrelvir treatment shows no link to reduced long-COVID risk, study reveals

In a recent study published in the Journal of Medical Virology, researchers investigated whether using nirmatrelvir during acute coronavirus disease 2019 (COVID-19) lowers the likelihood of developing post-acute COVID-19 (PASC) symptoms. They also investigated whether rebound after treatment was associated with PASC.

​​​​​​​Study: Association of nirmatrelvir for acute SARS-CoV-2 infection with subsequent Long COVID symptoms in an observational cohort study

Oral nirmatrelvir/ritonavir is authorized to treat COVID-19; however, its effect on PASC risk is uncertain. Unexplained symptoms characterize PASC. Vaccination reduces PASC danger but cannot eradicate it. Recent research indicates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persistence in PASC patients, including extended gastrointestinal shedding, SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in exosomes, and persistent SARS-CoV-2 proteins or ribonucleic acid (RNA). Nirmatrelvir, a new SARS-CoV-2 primary protease inhibitor implemented orally, may lower SARS-CoV-2 load and develop severe disease in high-risk, unvaccinated, non-hospitalized individuals.

Study Methodology

In the present study, researchers conducted a web-based observational study as a subset of the Covid Citizen Science (CCS) study, including more than 100,000 individuals.

From March to August 2022, the team included vaccinated, non-hospitalized, non-pregnant individuals with documentation of their first SARS-CoV-2 positive polymerase chain reaction (PCR) result. They established nirmatrelvir/ritonavir therapy through the oral route during an acute infection. They queried patient-reported PASC symptoms, symptomatic rebound, and PCR positivity rebound three months following the SARS-CoV-2 infection in subsequent surveys.

The team conducted the research through digital invitations to Eureka participants, oral messages, and referrals from partnered organizations. Participants completed surveys at study initiation and follow-up based on data obtained between 26 March 2020 and 22 December 2022. Only individuals who replied to questions related to PASC symptoms in November and December 2022 had their outcomes determined. The team defined the primary study outcome as the presence of one self-reported persistent COVID-19 symptom three months after the initial SARS-CoV-2-positive report.

The team excluded individuals who received molnupiravir, remdesivir, or monoclonal antibodies and hospitalized and pregnant women. They examined the relationship between nirmatrelvir medication and PASC among individuals living in the United States who were at risk for severe COVID-19. Participants who used nirmatrelvir were encouraged to participate in a survey-based assessment during December 2022 assessing for rebound symptomatology or SARS-CoV-2 positivity.

The team considered demographics, medical history, immunization history, and lifestyle factors. They performed logistic regression modeling to estimate the odds ratios (ORs), adjusted for age, gender, time since SARS-CoV-2 tested positive, and the propensity score’s cubic spline. They conducted the study with the inverse likelihood of treatment weighting and limited the inclusion criteria to US residents at high risk of severe COVID-19.

Key Findings on Nirmatrelvir and PASC Symptoms

The study included 4,684 individuals who had their initial positive SARS-CoV-2 test results during the SARS-CoV-2 Omicron variant predominance, among whom 988 (21%) received nirmatrelvir, whereas 3,696 (79%) did not. The participants completed the survey after five months of acute infection; the median participant age was 55 years; 66% of them were female. Five months after the acute infection, nirmatrelvir therapy was unrelated to PASC symptoms (OR, 1.2).

The team found no associations between rebound symptomatology or PCR positivity with PASC symptoms among 666 patients who responded to the rebound questions (OR, 1.3). Incorporating demographics, prior drug use, and medical history yielded similar results (OR, 1.2). Similarly, analysis using the inverse probability of treatment weighting method produced similar results (OR: 1.2). Among nirmatrelvir recipients, 57/353 (16%) experienced PASC symptoms compared to 176/1,258 (14%) non-recipients (OR, 1.2).

Fatigue, shortness of breath, disorientation, headache, and changed taste and smell were among the most commonly reported symptoms. Restricting high-risk individuals produced comparable findings for the sensitive (968 treated and 3,326 untreated individuals; OR: 1.1) and specific (890 treated and 2,840 untreated individuals; OR: 1.1) categories. The median number of PASC symptoms reported by nirmatrelvir recipients was one, compared to two among non-recipients. A few individuals in each group experienced ≥1.0 severe to very severe PASC symptoms.

Rebound Symptoms and PASC Analysis

In a rebound survey of 666 nirmatrelvir recipients, 21% had rebound symptoms. Rebound test positivity was observed in 26% of individuals who repeated SARS-CoV-2 antigen testing following a negative result and completing therapy. Among those polled, 26% reported rebound symptoms or test positives. In the rebound group, 11% reported one or more PASC symptoms, compared to 8.3% in the non-rebound group. The odds ratios for symptoms (OR, 1.2) and test-positives (OR, 1.5) were similar. The results were comparable for those who finished the entire 10-dose course of nirmatrelvir (OR, 1.2) and those who did not recover completely.

Conclusions and Implications

The study findings showed that oral nirmatrelvir therapy and rebound after treatment after acute SARS-CoV-2 infection were not associated with PASC symptoms. Treatment was unrelated to less or more severe symptoms and was not associated with rebound symptoms or a positive test following treatment. Higher viral loads and extended viral shedding are associated with PASC risk, and nirmatrelvir causes faster SARS-CoV-2 clearance, supporting the concept that nirmatrelvir may prevent PASC. However, there was no statistically significant difference in PASC prevalence between those who had rebounded and those who did not.