Abstract
BACKGROUND
The oral protease inhibitor nirmatrelvir has shown substantial efficacy in high-risk, unvaccinated patients infected with the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data regarding the effectiveness of nirmatrelvir in preventing severe coronavirus disease 2019 (Covid-19) outcomes from the B.1.1.529 (omicron) variant are limited.
METHODS
We obtained data for all members of Clalit Health Services who were 40 years of age or older at the start of the study period and were assessed as being eligible to receive nirmatrelvir therapy during the omicron surge. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of nirmatrelvir treatment with hospitalization and death due to Covid-19, with adjustment for sociodemographic factors, coexisting conditions, and previous SARS-CoV-2 immunity status.
RESULTS
A total of 109,254 patients met the eligibility criteria, of whom 3902 (4%) received nirmatrelvir during the study period. Among patients 65 years of age or older, the rate of hospitalization due to Covid-19 was 14.7 cases per 100,000 person-days among treated patients as compared with 58.9 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.27; 95% confidence interval [CI], 0.15 to 0.49). The adjusted hazard ratio for death due to Covid-19 was 0.21 (95% CI, 0.05 to 0.82). Among patients 40 to 64 years of age, the rate of hospitalization due to Covid-19 was 15.2 cases per 100,000 person-days among treated patients and 15.8 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.74; 95% CI, 0.35 to 1.58). The adjusted hazard ratio for death due to Covid-19 was 1.32 (95% CI, 0.16 to 10.75).
CONCLUSIONS
Among patients 65 years of age or older, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir than among those who did not. No evidence of benefit was found in younger adults.
Discussion
At the beginning of the surge of the omicron variant in January 2022, the Israeli authorities decided to pursue two lines of defense to protect the vulnerable and high-risk populations from severe Covid-19: a second booster dose9 and antiviral therapy. Treatment with nirmatrelvir is currently recommended by the National Institutes of Health (NIH) as the first choice for antiviral therapy for nonhospitalized adults who are at high risk for disease progression, regardless of vaccination status.10 Nevertheless, the NIH stated that data on the clinical efficacy of nirmatrelvir against the omicron variant are lacking,11 despite in vitro studies that showed potent inhibition of this variant by nirmatrelvir.12-15
Our study suggests that during the omicron surge, the rates of hospitalization and death due to Covid-19 were significantly lower among adults 65 years of age or older who had received treatment with nirmatrelvir than among younger adults who had received such treatment, regardless of whether a patient had previous SARS-CoV-2 immunity. An observed difference in the efficacy of nirmatrelvir treatment between patients who were 65 years of age or older and those who were younger than 65 years of age was also shown in the published subgroup analysis of the EPIC-HR trial.4 As expected, the observed risk of hospitalization due to Covid-19 in our study (which was conducted during the omicron-predominant period) was substantially lower than that reported in the EPIC-HR trial during the delta wave.16 However, within this older age group, the incidence of events was higher in the subgroup of patients without previous SARS-CoV-2 immunity (277 of 3318 patients [8%]) than in the subgroup with previous immunity (505 of 39,503 patents [1%]).
Our study has several limitations. As in any retrospective cohort study, various confounders may have caused bias in the observed effectiveness. We attempted to overcome biases in the risk of hospitalization by adjusting for the variables that are known to affect severe Covid-19 outcomes. Nevertheless, we may not have measured, or corrected adequately for, some sources of residual confounding and selection bias, such as differences in early diagnosis and differential access to nirmatrelvir therapy.17 Our study showed that only a minority of patients who were identified as high risk and eligible for nirmatrelvir therapy received the antiviral therapy. We do not know why the other eligible patients did not receive treatment, and there may be some selection mechanism that is not explained by the observed confounders; therefore, this observation remains our primary concern regarding residual bias.
We assume that the patients who were likely to be hospitalized because of severe symptoms were systematically treated at a higher rate. Since these symptoms were not reported consistently, it is likely that the treatment effect was underestimated in this study. Moreover, there is a concern that many of the hospitalizations occurred during the first 2 days of follow-up (Figure 2A), which may have resulted in bias if patients who were unwell enough to be hospitalized very soon after the positive PCR test were more or less likely to receive nirmatrelvir treatment. The sensitivity analysis, which assessed the effect size of nirmatrelvir treatment beginning on day 3 of follow-up, showed a hazard ratio of 0.28 (95% CI, 0.15 to 0.55); this result was similar to that of the main analysis, which suggests that this bias does not explain a large proportion of the effectiveness.
The EPIC-HR trial did not show a substantial effect of the treatment during the first 2 days of follow-up. However, patients who were likely to be hospitalized within 2 days after randomization were excluded.4 As a result, the clinical trial did not provide evidence regarding whether the drug had a more immediate effect. It should be noted that the subjective clinical impression of the treating physicians at CHS has been that the effect occurs quickly after nirmatrelvir administration.
A further limitation of our study is the heterogeneity of degrees of immunity in the subgroup of patients with previous immunity, including differences in the time since the patient’s last vaccine dose. This group included patients with immunity induced by infection, vaccination, or both, and any waning of such immunity over time was not taken into account. Nevertheless, the results seen in the subgroup of patients 65 years of age or older who had no previous immunity are similar to those seen in the EPIC-HR trial.
It should be noted that the evaluation of adverse events and safety data reports was beyond the scope of this study. Future studies will be needed to assess the short- and long-term safety of nirmatrelvir treatment in real-world settings.
During the omicron variant surge, among adults 65 years of age or older, the rates of severe Covid-19 outcomes were significantly lower among those who received nirmatrelvir than among those who did not receive nirmatrelvir. However, no evidence of benefit was found in younger adults.
SOURCE: NEJM
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