Discussion
SARS, infection, deaths, subvariants
VIRUS, ASYMPTOMATIC COVID-19, HEMATOLOGIC MALIGNANCY, CNS INFECTIONS, COVID-19 INFECTION, INFECTION
We identified several COVID-19 cases among high-risk patients in our health system who had received T/C for pre-exposure prophylaxis. However, when we compared those who had contracted COVID-19 prior to receiving T/C prophylaxis with those infected after, patients with infection after receiving T/C were only a quarter as likely to be hospitalized for COVID-19 and were also significantly less likely to be admitted to the ICU.It is difficult to assess, however, the impact of T/C prophylaxis on the lower hospitalization rate in our cohort. Almost all patients who had COVID-19 after receiving prophylactic T/C were also offered additional treatment for symptomatic COVID-19, including updated monoclonal antibodies or antiviral therapies, and nearly three-quarters had received at least three COVID-19 vaccine doses, including 37% who had received four. In addition to the availability of additional vaccine doses and a greater range of effective COVID-19 therapeutics over time, there have also been rapidly changing subvariants of varying severity and increasing immune evasiveness, further complicating the interpretation of therapeutic effectiveness. Monoclonal antibodies targeting the regions of the spike protein of the SARS CoV-2 virus under evolutionary pressure have not been studied at a pace that meets the speed of the evolution of variants in the COVID-19 pandemic. Our study underscores the inherent challenge of assessing real-world efficacy of T/C outside of a clinical trial given the rapidly evolving SARS CoV-2 pandemic.Our findings differ from those of the initial clinical trial of T/C which had demonstrated an 83% risk reduction for symptomatic COVID-19 infection among recipients of T/C. However, the PROVENT trial largely excluded patients with solid organ transplantation or hematologic malignancy, and less than 4% of the study population was identified as having an immunocompromising condition [Since T/C has been in use, several studies have shown T/C recipients to have contracted COVID-19. Among a study of 416 kidney transplant recipients who received T/C in France, there were 39 cases of COVID-19 infection and 2 deaths post-TC, but the drug was dosed at 150 mg of tixagevimab and 150 mg of cilgavimab, supporting that the lower dose was insufficient to provide protection against Omicron [Our study addresses in detail the therapeutics given in each group and acknowledges how these treatments may have had an important influence on patient outcomes. We also highlight the significant role of the epidemiologic curve in assessing case rates during the Omicron era, and the importance of understanding community transmission rates over time in terms of assessing effectiveness of various interventions.Our study has several limitations. First, although we used multiple data sources to identify cases, patients receiving COVID-19 care at other health care systems may not have been captured in our data. Second, because the limitations imposed by the use of retrospective data, it was not possible to conduct more rigorous analyses that might have allowed us to determine the relative contributions of T/C, underlying patient conditions, prior immunity to COVID-19, vaccine, circulating variants, and antiviral and monoclonal antibody treatment to the risk of developing COVID-19. However, the associations for which we were able to identify a significant effect in the main analysis had large E-values ranging from 5.51 and 19.49, indicating that the level of association between factors such as prior infection with COVID-19 and both the T/C exposure and outcomes of interests would not plausibly reach such levels of association.Despite these limitations, our findings demonstrate that high-risk patients who have received T/C pre-exposure prophylaxis continue to develop symptomatic COVID-19 infections in the Omicron era. We note that those were infected with COVID-19 after having received T/C in our study had fewer hospitalizations and ICU stays, they also had more doses of COVID vaccines and received therapeutics predicted to be effective for Omicron. While no patients in our cohort experienced direct harm from receiving T/C, our results raise questions about the ongoing value of T/C pre-exposure prophylaxis. Given the many rapidly changing aspects of the COVID-19 pandemic, including the evolution of variants and subvariants, the protection offered by additional vaccine doses, and the development of effective antivirals and therapeutic monoclonal antibodies, we are unable to truly assess the contribution of T/C to the improved outcomes among patients without a rigorous clinic trial. Such a trial, however, would be difficult to perform and would run the risk of being rapidly outdated. As a result, decisions regarding the significant resources required to administer this drug unfortunately continue to depend on data from 