A recently published study in The lancet reported the practical efficacy of oral antiviral therapies nirmatrelvir plus ritonavir and molnupiravir in the Omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on a 2019 observational study of coronavirus disease (COVID-19) patients in Hong Kong.
Most of the evidence for the efficacy of oral antivirals such as nirmatrelvir plus ritonavir and molnupiravir comes from clinical trials conducted before SARS-CoV Omicron (B.1.1.529) became the predominant circulating variant. Clinical trials in over 20 countries have shown that early administration of these two oral antiviral therapies to people with mild to moderate COVID-19 symptoms reduces the risk of hospitalization and mortality by 30-89%.
A large number of the clinical trials of nirmatrelvir plus ritonavir and molnupiravir were conducted in unvaccinated, unhospitalized individuals who were at risk of progression from mild or moderate COVID-19 symptoms to severe disease. In addition, most of the studies were conducted during the spread of the SARS-CoV-2 delta (B.1.617.2) variant. Therefore, the practical effectiveness of these therapies needs to be evaluated based on the emerging SARS-CoV-2 variants and the vaccination status of individuals.
About the study
In the present study, researchers used the Hong Kong Hospital Authority database to access information on confirmed SARS-CoV-2 cases and associated demographics, diagnoses, treatments prescribed, COVID-19 vaccination status, laboratory testing, hospitalization status, and registration collect deaths. The study was conducted between January and June 2022, the period of dominance of the SARS-CoV-2 omicron variant.
Subjects 18 years and older with positive reverse transcriptase polymerase chain reaction (RT-PCR) tests confirming SARS-CoV-2 infection were included in the study. Patients received molnupiravir or nirmatrelvir plus ritonavir within five days of onset of mild to moderate symptoms.
Risk factors such as diabetes, obesity, other chronic diseases, age (older than 60 years) and incomplete vaccination were taken into account as criteria for antiviral administration. The study excluded people being treated with medications that may have contraindications to nirmatrelvir plus ritonavir. Patients with severe renal or hepatic impairment were also excluded to avoid confounding the results.
The primary analysis was based on a retrospective cohort study, while the internal validation sensitivity analysis was based on a case-control study design. Participants were divided into two groups based on the prescription of molnupiravir or nirmatrelvir plus ritonavir. The date of positive SARS-CoV-2 or the onset of symptoms, whichever came first, was considered the index date. The treatment cohort was matched to a control cohort that included SARS-CoV-2 positive subjects who were not prescribed molnupiravir or nirmatrelvir plus ritonavir.
The retrospective cohort study and the case-control study measured three outcomes – all-cause mortality, hospitalization for COVID-19, and a composite outcome consisting of the need for intensive care unit (ICU) or invasive mechanical ventilation (IMV) or in-hospital mortality. The cohort study also included an additional endpoint of individual hospital outcomes consisting of mortality, initiation of IMV, or need for intensive care.
The results showed that early administration of the oral antiviral drugs molnupiravir or nirmatrelvir plus ritonavir significantly reduced the risk of mortality compared to no treatment with either antiviral therapy. In addition, nirmatrelvir plus ritonavir also reduced the risk of hospitalization for COVID-19.
Early administration of the two oral antiviral therapies was associated with reduced mortality and reduced risk of hospitalization in patients aged 60 years and older. Molnupiravir administration resulted in reduced initiation of IMV. Updated clinical trials showed that nirmatrelvir plus ritonavir reduced mortality and hospital risk by 51% in unvaccinated individuals or fully vaccinated COVID-19 patients with at least one risk factor.
The study found that molnupiravir users were older and more likely to be incompletely vaccinated than nirmatrelvir plus ritonavir users. The authors believe that this result is best explained by the first-mover advantage of molnupiravir and that nirmatrelvir plus ritonavir is not as commonly prescribed to the elderly because of its interactions with various other drugs. However, later guidance promotes nirmatrelvir plus ritonavir over molnupiravir as it significantly reduces the risk of hospitalization even in incompletely vaccinated patients.
In summary, the observational study conducted in Hong Kong during the dominance of SARS-CoV-2 sublineage Omicron BA.2.2 reported that early administration of the oral antiviral drugs nirmatrelvir plus ritonavir or molnupiravir reduced disease severity and significantly reduced the risk of mortality. Nirmatrelvir plus ritonavir also lowered the risk of hospitalization.
The authors noted that given the potential genotoxicity and mutational risks of molnupiravir and concerns about the development of antiviral resistance from rapidly mutating SARS-CoV-2, further clinical trials and increased pharmacovigilance to monitor the safety of oral antiviral drugs are needed.
- Wong, CKH, Au, ICH, Lau, KTK, Lau, EHY, Cowling, BJ, & Leung, GM (2022). Real-world efficacy of molnupiravir and nirmatrelvir plus ritonavir on mortality, hospitalizations, and hospital outcomes in outpatient, outpatients with confirmed SARS-CoV-2 infection during the Omicron wave in Hong Kong: an observational study. The lancet. doi: https://doi.org/10.1016/s0140-6736(22)01586-0 https://www.sciencedirect.com/science/article/pii/S0140673622015860