Real-world effectiveness of pharmacotherapies for the prevention of severe and fatal COVID-19

Abstract

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was a global health emergency that led to significant morbidity and mortality. In early 2022, the emergence of the Omicron variant resulted in widespread outbreaks even in regions with prior success of controlling the pandemic, including Hong Kong where an unusually high COVID-19 fatality rate was observed at the time. This may be attributed to low vaccination coverage among older individuals and vaccine hesitancy. Various pharmacotherapies to prevent severe and fatal illness from COVID-19 were developed, including vaccines (BNT162b2, CoronaVac), monoclonal antibodies for pre-exposure prophylaxis (tixagevimab-cilgavimab), and oral antivirals for preventing disease progression after infection (molnupiravir, nirmatrelvir-ritonavir). Knowledge gaps remained regarding their effectiveness against the Omicron variant and among patients encountered in real-world practice. Firstly, randomised trials of COVID-19 vaccines were mainly conducted before Omicron emerged among healthier populations. Considering immune evasion of the Omicron variant and higher prevalence of risk factors for severe COVID-19, further investigation into vaccine effectiveness during an Omicron outbreak among the general population and high-risk groups was needed. Secondly, immunocompromised individuals may have suboptimal response to COVID-19 vaccines and require additional therapies for prevention. Although tixagevimab-cilgavimab reduced symptomatic SARS-CoV-2 infection among unvaccinated adults before Omicron emerged, data among vaccinated, immunocompromised individuals during an Omicron outbreak was not available. Thirdly, although randomised trials showed efficacy of molnupiravir and nirmatrelvir-ritonavir in non-hospitalised patients for the treatment of COVID-19, data among vaccinated, hospitalised adults were limited. These unanswered questions could hinder the adoption of these pharmacotherapies in practice. In this thesis, observational studies were conducted using electronic medical records databases in Hong Kong, to generate real-world evidence to address the aforementioned questions. The key findings were that: (i) BNT162b2 and CoronaVac were effective in reducing the risks of COVID-19-related hospitalisation, critical illness, and mortality during an Omicron BA.2 outbreak, and timely administration of a third dose could further reduce such risks despite a decline in vaccine effectiveness over time, (ii) tixagevimab-cilgavimab was effective in reducing the risk of SARS-CoV-2 infection among immunocompromised individuals during an Omicron BA.2/BA.5-dominant period; and (iii) molnupiravir and nirmatrelvir-ritonavir were effective in reducing the risk of mortality among patients hospitalised for COVID-19. Consistent results were observed among older people and those with multiple comorbidities. This research provided evidence to promote vaccination among older individuals with chronic diseases, by instilling confidence towards the effectiveness of COVID-19 vaccines and raising awareness on the importance of receiving booster doses, thereby reducing vaccine hesitancy. The findings bridged evidence gaps regarding the effectiveness of CoronaVac against Omicron, and the optimal window for receiving a booster dose. The results also demonstrated the role of tixagevimab-cilgavimab for pre-exposure prophylaxis among the immunocompromised population in regions where Omicron BA.2/BA.5 remained dominant, and informed clinical practice and policies regarding the use of oral antivirals among vaccinated adults hospitalised for COVID-19. Last but not least, methodologies employed in this thesis can be adapted for timely evaluation of real-world effectiveness of vaccines and other preventive pharmacotherapies in future infectious disease pandemics.