Comparative Efficacy of Combination Treatment with Nirmatrelvir-Ritonavir and Remdesivir Versus Remdesivir Monotherapy in Hospitalised COVID-19 Patients: A Target Trial Emulation Study

Abstract

Background: Remdesivir (Veklury®) and nirmatrelvir-ritonavir (Paxlovid®) are the two commonly used antiviral agents for hospitalised patients suffering from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Hong Kong. Although current therapeutic studies demonstrate the clinical effectiveness of remdesivir in coronavirus disease 2019 (COVID-19) patients by shortening the time to clinical recovery and hospital stay, there is a significant proportion of high-risk individuals in Hong Kong who fail to achieve optimal clinical response after a course of standard antiviral monotherapy regimen. Preclinical data has shown the in vitro synergy between remdesivir and nirmatrelvir-ritonavir, which can potentially hasten the virologic and clinical recovery in hospitalised patients with COVID-19.

Methods: We conducted a target trial emulation study to critically analyse the current evidence of a combination of remdesivir and nirmatrelvir-ritonavir versus remdesivir alone in the management of COVID-19 in Hong Kong and dissect the aspects of their safety and efficacy. This study utilised the territory-wide electronic health records databases. Patients aged ≥ 18 years with an initial diagnosis of COVID-19 who received either combination treatment with nirmatrelvir-ritonavir and remdesivir or remdesivir between 16 March 2022 and 31 December 2022 and were hospitalised within five days before the date of drug treatment were included in the study.

Results: A total of 1,843 participants (nirmatrelvir-ritonavir and remdesivir: 251; remdesivir: 1,592 were included in the study cohort after inclusion and exclusion. After a median follow-up of 90 days, combination users of nirmatrelvir-ritonavir and remdesivir had a significantly lower risk of mortality (absolute risk reduction [ARR] 8·22; 95% confidence interval [CI], 3·05-13·40) when compared to individuals using remdesivir alone. However, there are no statistically significant differences in terms of Intensive Care Unit (ICU) admission, ventilatory support, myocardial infarction, ischaemic stroke, and acute liver and kidney injury between these two groups.

Conclusions: Combination treatment of nirmatrelvir-ritonavir and remdesivir is an effective strategy for COVID-19, which confers a lower risk of mortality compared to remdesivir monotherapy with a good safety profile.

Funding: The Health & Medical Research Fund Commissioned Research on COVID-19 (COVID1903010), The Government of the Hong Kong SAR, China. Donations from Mrs Rosanna Gaw and Dr Cheuk Shu Kwan.

Declaration of Interest: EYFW has received research grants from the Food and Health Bureau of the Government of the Hong Kong Special Administrative Region, the Hong Kong Research Grants Council of the Government of the Hong Kong SAR, Narcotics Division, Security Bureau of the Government of the Hong Kong SAR, and National Natural Science Foundation of China, outside the submitted work. ICKW reports research funding from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong Research Grants Council of the Government of the Hong Kong SAR, the Hong Kong Health and Medical Research Fund, the National Institute for Health Research in England, the European Commission, and the National Health and Medical Research Council in Australia, consulting fees from IQVIA and World Health Organization, payment for expert testimony for Appeal Court of Hong Kong and is a non-executive director of Jacobson Medical in Hong Kong and Therakind in England, outside of the submitted work. ICKW reports role as member of Pharmacy and Poisons Board in Hong Kong, the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization, and the Advisory Panel on COVID-19 Vaccines of the Hong Kong Government. EWYC reports grants from the Hong Kong Research Grants Council of the Government of the Hong Kong SAR, Research Fund Secretariat of the Food and Health Bureau, National Natural Science Fund of China, Wellcome Trust, Bayer, Bristol-Myers Squibb, Pfizer, Janssen, Amgen, Takeda, RGA Reinsurance Company, AstraZeneca, Narcotics Division of the Security Bureau of the Hong Kong Special Administrative Region, Innovation and Technology Commission of the Government of the Hong Kong Special Administrative Region, Novartis, National Health and Medical Research Council Australia; honorarium from Hospital Authority; outside the submitted work. EWYC reports unpaid role of president of International Society for Pharmacoeconomics and Outcomes Research (ISPOR), Hong Kong Regional Chapter. IFNH is an advisory board member for Pfizer, MSD, GSK, Moderna and AstraZeneca. IFNH received research grants from the Hong Kong Research Grants Council of the Government of the Hong Kong SAR and the Hong Kong Health and Medical Research Fund. IFNH received travel grant from MSD and Pfizer to attend scientific meetings. IFNH reports role as co- convenor of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization, and member of the COVID-19 Expert Advisory Panel of the Government of the HKSAR, the Advisory Panel on COVID-19 Vaccines of the Government of the HKSAR, and the Scientific Committee on Vaccine Preventable Diseases of the Government of the HKSAR. IFNH reports role as Associated Editor for the journals Vaccine, and Diagnostics.

Ethical Approval: This study was approved by the Central Institutional Review Board of the Hospital Authority of Hong Kong (CIRB-2021-005-4) and the DH Ethics Committee (LM171/2021).

Keywords: SARS-CoV-2, COVID-19, nirmatrelvir-ritonavir, remdesivir, combination therapy, Hong Kong