Assessment of Nirmatrelvir-Ritonavir Effects on Acute and Post-Acute COVID-19 Illness in US Adolescents: Target Trial Emulation

IMPORTANCENirmatrelvir-ritonavir, an efficacious treatment for acute COVID-19, has yielded conflicting evidence regarding its effectiveness in preventing Long COVID among adults. The effectiveness of nirmatrelvir-ritonavir in adolescents in real-world settings is not well understood. OBJECTIVETo evaluate the effectiveness of nirmatrelvir-ritonavir in adolescents aged 12 to 20 years given within the first five days of acute COVID-19 illness on illness severity during the acute (days 0 to 27) and post-acute phases (days 28 to 179). DESIGN, SETTING, AND PARTICIPANTSThis target trial emulation used the electronic health records (EHR) data from twenty-nine medical institutions participating in the NIHs RECOVER consortium. We included data collected between April 1, 2022 and December 31, 2023, and included all patients with a SARS-CoV-2 infection who were not hospitalized on the day of entry. Those who were treated with oral nirmatrelvir-ritonavir within 5 days after the positive test (n=2,923) and those who did not received nirmatrelvir-ritonavir within 5 days after the positive test during the acute phase of SARS-CoV-2 infection (control group, n=31,947) were identified. EXPOSURESTreatment with nirmatrelvir-ritonavir based on prescription records. MAIN OUTCOMES AND MEASURESWe used modified Poisson regression models for binary outcomes to examine the effects of nirmatrelvir-ritonavir on acute phase hospitalization, emergency department (ED) visits, and outpatient visits as well as progression to moderate or severe acute illness among individuals treated with nirmatrelvir-ritonavir compared to control counterparts. Additionally, we assessed the medications associations with 16 conditions and symptoms during the acute phase of illness and its subsequent association with specific Long COVID diagnostic code U09.9 during the post-acute phase. We reported the absolute risks and estimated the relative risks (RRs), with adjustments made for demographic variables, clinical characteristics, and healthcare utilization, using propensity score matching. RESULTSThe study cohort included 34,870 adolescents (median [Q1, Q3] age 16.0 [14.0, 18.0]); 46.0% male and 43.2% Non-Hispanic White. Among these patients, 2,923 were treated with nirmatrelvir-ritonavir within 5 days of cohort entry and 31,947 received no treatment. The absolute rates were 0.58% vs. 0.96% for hospitalization, 74.17% vs. 82.66% for outpatient visits, 1.81% vs. 2.28% for ED visits, 3.08% vs. 3.99% for moderate/severe acute illness, and 0.21% vs. 0.20% for long COVID diagnosis in the treatment vs. control group. After propensity score matching, during acute-phase period, compared to the control group, nirmatrelvir-ritonavir was associated with reduced risk of any hospitalization (relative risk (RR) 0.48; 95% confidence interval (CI) 0.29-0.80), outpatient visit (RR 0.86; 95% CI 0.82-0.90), and moderate/severe acute illness (RR 0.69; 95% CI 0.56-0.87). Additionally, nirmatrelvir-ritonavir was associated with reduced risk of 7 of 16 specified conditions in chest pain (RR 0.41; 95% CI 0.26-0.63), fatigue and malaise (RR 0.49; 95% CI 0.32-0.76), generalized pain (RR 0.65; 95% CI 0.45-0.95), headache (RR 0.60; 95% CI 0.44-0.83), mental health (RR 0.56; 95% CI 0.39-0.80), musculoskeletal (RR 0.63, 95% CI 0.43-0.94), and respiratory signs and symptoms (RR 0.61, 95% CI 0.52-0.71). No evidence was found to suggest that the treatment was associated with the risk of long COVID diagnosis U09.9 (RR 0.96, 95% CI 0.40-2.32). CONCLUSIONS AND RELEVANCEThis study found that treatment with nirmatrelvir-ritonavir in adolescents within 5 days of SARS-CoV-2 infection, was associated with reduced risk of acute-phase COVID-19 illness and subsequent healthcare utilization. However, treatment was not associated with a lower risk of Long COVID diagnosis. Key PointsO_ST_ABSQuestionC_ST_ABSDoes treatment with nirmatrelvir-ritonavir reduce the acute COVID-19 illness severity and the risk of developing Long COVID in adolescents aged 12 to 20 years? FindingsIn this target trial emulation study of 34,870 adolescents with SARS-CoV-2 infection who were not hospitalized on the cohort entry day, 2,923 who were treated with nirmatrelvir-ritonavir exhibited lower acute illness severity including reduced risk of 7 of 16 specified conditions and symptoms, as well as reduced risk of acute-phase hospitalization and outpatient visits, compared with 31,947 who received no treatment. The association with reduced risk of Long COVID was not observed in this study. MeaningIn adolescents, nirmatrelvir-ritonavir appears to be effective at reducing the severity of acute COVID illness but was not associated with the risk of developing Long COVID.