Nirmatrelvir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records

Abstract

Objective To estimate the effectiveness of nirmatrelvir, compared with no treatment, in reducing admission to hospital or death at 30 days in people infected with the SARS-CoV-2 virus and at risk of developing severe disease, according to vaccination status and history of previous SARS-CoV-2 infection. Design Emulation of a randomized target trial with electronic health records. Setting Healthcare databases of the US Department of Veterans Affairs Participants 256 288 participants with a SARS-CoV-2 positive test result and at least one risk factor for developing severe covid-19 disease, between 3 January and 30 November 2022. 31 524 were treated with nirmatrelvir within five days of testing positive for SARS-CoV-2 and 224 764 received no treatment. Main outcome measures The effectiveness of starting nirmatrelvir within five days of a positive SARS-CoV-2 test result versus no treatment in reducing the risk of admission to hospital or death at 30 days was estimated in those who were not vaccinated, in those who received one or two doses of vaccine, and those who received a vaccine booster and, separately, in participants with a primary SARS-CoV-2 infection or reinfection. The inverse probability weighting method was used to balance personal and health characteristics between the groups. Relative risk and absolute risk reduction were computed from cumulative incidence at 30 days, estimated by weighted Kaplan-Meier estimator. Results Among people who were not vaccinated (n=76 763; 5338 nirmatrelvir and 71 425 no treatment), compared with no treatment, the relative risk of nirmatrelvir in reducing admission to hospital or death at 30 days was 0.60 (95% confidence interval 0.50 to 0.71); the absolute risk reduction was 1.83% (95% confidence interval 1.29% to 2.49%). The relative risk and absolute risk reduction, compared with no treatment, were 0.65 (0.57 to 0.74) and 1.27% (0.90% to 1.61%), respectively, in people who received one or two doses of vaccine (n=84 620; 7989 nirmatrelvir and 76 631 no treatment); 0.64 (0.58 to 0.71) and 1.05% (0.85% to 1.27%) in individuals who received a booster dose of vaccine (n=94 905; 18 197 nirmatrelvir and 76 708 no treatment); 0.61 (0.57 to 0.65) and 1.36% (1.19% to 1.53%) in participants with a primary SARS-CoV-2 infection (n=228 081; 26 350 nirmatrelvir and 201 731 no treatment); and 0.74 (0.63 to 0.87) and 0.79% (0.36% to 1.18%) in participants who were reinfected with the SARS-CoV-2 virus (n=28 207; 5174 nirmatrelvir and 23 033 no treatment). Nirmatrelvir was associated with a reduced risk of admission to hospital or death in those aged ≤65 years and > 65 years; in men and women; in black and white participants; in those with 1-2, 3-4, and ≥5 risk factors for progression to severe covid-19 illness; and in those infected during the omicron BA.1 or BA.2 predominant era, and the BA.5 predominant era. Conclusions In people with SARS-CoV-2 infection who were at risk of developing severe disease, compared with no treatment, nirmatrelvir was associated with a reduced risk of admission to hospital or death at 30 days in people who were not vaccinated, vaccinated, and had received a booster vaccine, and in those with a primary SARS-CoV-2 infection and reinfection.

Risk of severe coronavirus disease 2019 despite vaccination in patients requiring treatment with immune‐suppressive drugs: A nationwide cohort study of US Veterans

“…This study shows the benefit of treatment with antiviral drugs in immune‐suppressed, vaccinated patients, in a cohort with high frequencies of relevant comorbidities. This result is consistent with conclusions of other studies that compared untreated patients in cohorts in which vaccination was universal or very common, 20–23 including two studies using nationwide VA data that were not focused on but did include immune‐suppressed patients 22,23 . All four of these studies included propensity score matching with untreated controls in order to focus on the effect of nirmatrelvir/ritonavir, and all included hospitalization or death within 30 days in their primary outcomes.…”

Effectiveness of nirmatrelvir‐ritonavir on severe outcomes of COVID‐19 in the era of vaccination and Omicron: An updated meta‐analysis

“…Four studies were considered at moderate risk of bias. 20,34,58,63 All other studies were considered at serious or critical risk of bias, mostly due to high risk of residual confounding or important other biases, such as immortal time bias or selection bias. One randomized trial was judged as low risk of bias 46 ; the other as high risk of bias, due to non-blinding, imbalance between the treatment groups and subjective measurement of outcomes.…”

Nirmatrelvir/ritonavir for the treatment of immunocompromised adult patients with early‐stage symptomatic COVID‐19: A real‐life experience

“…9 In view of this evidence, the Food and Drug Administration and the European Medicines Agency issued in December 2021 and January 2022, respectively, the emergency use authorization (EUA) for NMV/r to treat mild-to-moderate laboratoryconfirmed COVID-19 in nonhospitalized patients at high risk of clinical progression, which include those who are immunocompromised. 10 In spite of the encouraging results from the EPIC-HR trial and the growing number of real-life studies performed in the general population, [11][12][13][14] the need of co-administration with ritonavir (a potent inhibitor of cytochrome CYP3A4) raises concerns about the potential for drug-to-drug interactions (DDIs) and associated adverse effects. 15 This circumstance has limited the use of NMV/r among patients receiving immunosuppressive therapies, thus narrowing their already limited options.…”