Dear Editor,
We read with great interest the recent article published in the Journal of Infection investigating the effectiveness of molnupiravir, nirmatrelvir–ritonavir, and sotrovimab in preventing hospital admission or death among COVID-19 patients.1 We noticed that despite the use of broad-spectrum antivirals (e.g. remdesivir), monoclonal antibodies, corticosteroids, hydroxychloroquine2 being attempted, only limited effectiveness was achieved in reducing mortality, along with financial and logistical limitations, preventing their widespread use. Hence, the pertinent question on whether the short-term evidence on the effectiveness of COVID-19 oral antivirals in reducing risk of mortality and hospitalizations holds true even in the post-acute phase, especially in a largely vaccinated global population in an Omicron-dominant setting, remains to be explored.3 Thus, by examining two cohorts of hospitalized patients from Hong Kong prescribed with either molnupiravir or nirmatrelvir–ritonavir, this longitudinal study aims to assess the benefits of both drugs in reducing all-cause mortality in COVID-19 vaccine recipients compared to non-recipients in an in-patient setting in the post-acute phase of infection.
In this retrospective cohort study, electronic health records of eligible patients were extracted from the Hospital Authority (HA), vaccination records and COVID-19-confirmed diagnosis records from Department of Health (DH), and death-related records from the Hong Kong Deaths Registry. The validity and coding accuracy of all the databases have been evaluated in many previous high-quality epidemiological studies and COVID-19 pharmacovigilance studies.4, 5, 6 All data were extracted with an anonymized personal identifier to protect patient confidentiality before performing analysis.
Incidence rates and their corresponding confidence intervals (CIs) for each outcome were calculated based on the Poisson distribution. The association between COVID-19 antivirals and outcome occurrence was further estimated using the Cox proportion hazards regression model. Subgroup analysis was also conducted in subgroups stratified by age, sex, Charlson’s Comorbidity index, and number of vaccination doses received. Several sensitivity analyses were performed to test the robustness of the main results. All the analyses in this study were two-tailed, and results were considered statistically significant with a P-value< 0.05. R version 4.0.3 (www.R-project.org) was used for all statistical analyses. Two investigators (BW, CIYC) conducted the statistical analyses independently for quality assurance. STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement checklists were followed to guide transparent reporting of the cohort study.
For the analysis, 30,040 hospitalized patients with documentation of COVID-19 positivetest or prescription records of either of the two COVID-19 oral antivirals, between 26 February and 30 September 2022, were included (Supplementary Fig. 1). After a median follow-up of 172 days, 3758 events of mortality were recorded among participants. After fine stratification weighting, the lowest incidence rates (95% CI) for all the three outcomes were observed in nirmatrelvir–ritonavir recipients. The characteristics of patients in each group are displayed in the Table 1. Fig. 1 summarizes the incidence rates and the corresponding risks in the post-acute phase (i.e. 21 days after first COVID-19 positive test) associated with all-cause mortality in each group. Significantly lower risks of all-cause mortality were associated with both molnupiravir [HR (95% CI): 0.89 (0.81–0.98)] and nirmatrelvir–ritonavir [HR (95% CI): 0.72 (0.62–0.84)]. However, only nirmatrelvir–ritonavir recipients experienced significantly lower risks of A&E admission [HR (95%CI): 0.76 (0.70–0.82)] and hospitalization [HR (95% CI): 0.82 (0.76–0.88).
Table 1.
Baseline characteristics of hospitalized COVID-19 patients after weighting.
| Non-recipients | Molnupiravir recipients | Nirmatrelvir–ritonavir recipients | SMD | |
|---|---|---|---|---|
| Number of individuals | 17,283 | 6153 | 6604 | |
| Age, years | 72.58 (18.22) | 73.11 (17.15) | 72.65 (16.48) | 0.020 |
| Sex, male | 9090 (52.6) | 3304 (53.7) | 3464 (52.4) | 0.017 |
| Charlson Comorbidity Index | 4.26 (2.54) | 4.36 (2.35) | 4.23 (2.42) | 0.036 |
| Number of vaccinations received | 0.051 | |||
| 0 | 5336 (30.9) | 2000 (32.5) | 2095 (31.7) | |
| 1 dose of BNT162b2 | 420 (2.4) | 143 (2.3) | 142 (2.1) | |
| 2–3 doses of BNT162b2 | 2309 (13.4) | 871 (14.2) | 820 (12.4) | |
| 1 dose of CoronaVac | 2579 (14.9) | 843 (13.7) | 987 (14.9) | |
| 2–3 doses of CoronaVac | 6640 (38.4) | 2296 (37.3) | 2560 (38.8) | |
| Comorbidities | ||||
| Cancer | 1806 (10.5) | 666 (10.8) | 734 (11.1) | 0.014 |
| Chronic Kidney Disease | 1789 (10.4) | 687 (11.2) | 575 (8.7) | 0.055 |
| Respiratory disease | 1646 (9.5) | 580 (9.4) | 640 (9.7) | 0.006 |
| Diabetes | 4918 (28.5) | 1806 (29.3) | 1847 (28.0) | 0.020 |
| Cardiovascular disease | 10,387 (60.1) | 3779 (61.4) | 3901 (59.1) | 0.032 |
| Dementia | 697 (4.0) | 251 (4.1) | 252 (3.8) | 0.009 |
| Medication use within 90 days | ||||
| Renin-angiotensin-system agents | 6390 (37.0) | 2315 (37.6) | 2411 (36.5) | 0.015 |
| Beta-blockers | 5029 (29.1) | 1866 (30.3) | 1871 (28.3) | 0.029 |
| Calcium channel blockers | 8658 (50.1) | 3102 (50.4) | 3234 (49.0) | 0.019 |
| Diuretics | 4202 (24.3) | 1546 (25.1) | 1573 (23.8) | 0.020 |
| Nitrates | 2098 (12.1) | 776 (12.6) | 761 (11.5) | 0.022 |
| Lipid-lowering agents | 8045 (46.5) | 2912 (47.3) | 3025 (45.8) | 0.020 |
| Insulins | 3115 (18.0) | 1123 (18.3) | 1181 (17.9) | 0.007 |
| Antidiabetic drugs | 4550 (26.3) | 1644 (26.7) | 1777 (26.9) | 0.009 |
| Oral anticoagulants | 1538 (8.9) | 579 (9.4) | 580 (8.8) | 0.015 |
| Antiplatelets | 5811 (33.6) | 2132 (34.7) | 2245 (34.0) | 0.015 |
| Immunosuppressants | 593 (3.4) | 227 (3.7) | 242 (3.7) | 0.009 |
| Medication use within 7 days after COVID-19 diagnosis | ||||
| Tocilizumab | 57 (0.3) | 13 (0.2) | 19 (0.3) | 0.015 |
| Baricitinib | 122 (0.7) | 45 (0.7) | 77 (1.2) | 0.032 |
| Remdesivir | 1935 (11.2) | 751 (12.2) | 834 (12.6) | 0.030 |
| Interferon beta-1b | 241 (1.4) | 90 (1.5) | 88 (1.3) | 0.008 |
| ICU admission within 7 days after COVID-19 diagnosis | 356 (2.1) | 143 (2.3) | 166 (2.5) | 0.021 |
| Ventilatory support within 7 days after COVID-19 diagnosis | 413 (2.4) | 113 (1.8) | 133 (2.0) | 0.026 |
All parameters are expressed in either frequency (percentage) or mean (SD).
SMD = Standardized mean difference.
Fig. 1.
Risk of all-cause mortality/hospitalization/A&E admission associated with different oral antiviral use at post-acute phase of infection. Incidence rate (cases/1000 person-years) with 95% confidence interval based on Poisson distribution. Hazard ratio with 95% confidence interval was obtained by Cox regression adjusted with weighting. CI = confidence interval; REF = reference level; A&E = accident and emergency.
Fig. 2 illustrates the results from the subgroup analyses for each group. Similar patterns of mortality risk reduction were identified in association with drug recipients over non-drug recipients, largely consistent with the main analysis. Consistent findings were observed across sexes, Charlson Comorbidity Index scores and vaccination status, and in patients aged ≥65. However, among patients aged <65, no such benefits of risk reduction were associated with either drugs. Notably, the outcomes of hospitalization and A&E admissions followed a similar trend (Supplementary Fig. 5) and results from the sensitivity analyses were also largely consistent with the main analysis (Supplementary Figs. 2–4).
Fig. 2.
Risk of all-cause mortality associated with different oral antiviral use in post-acute phase of infection within subgroups. Hazard ratio with 95% confidence interval was obtained by Cox regression adjusted with weighting. CI = confidence interval; REF = reference level; A&E = accident and emergency; CCI = Charlson’s Comorbidity index.
The findings of this study demonstrate the survival benefits of both molnupiravir and nirmatrelvir–ritonavir in reducing COVID-19-associated risk of all-cause mortality among hospitalized patients during the post-acute phase of COVID-19 infection compared to non-recipients. This is in addition to reducing short-term risk of mortality and hospitalization in the acute phase of infection as demonstrated by previous studies. To the best of our knowledge, this study is the first to evaluate the real-world benefits of both oral-antiviral drugs (molnupiravir and nirmatrelvir–ritonavir) against COVID-19-associated mortality in an in-patient cohort of 20,000 hospitalized patients in the post-acute phase. The advantage of an in-patient setting supports the reliability of the systematic documentation of patient data as electronic health records recorded in the medical database by the HA, facilitating analysis of follow-up data. Further, including vaccinated and unvaccinated patients in the study cohort enabled evaluation of the effect of prior immunization and its potential interaction with antiviral benefits. By defining the inclusion period for patient recruitment to capture the Omicron-dominant infection outbreak, an up-to-date pandemic setting was more accurately represented, and association of drug-effectiveness against the newer subvariants could be evaluated. Nevertheless, several limitations underlie this study. Firstly, the usual limitation of inability to establish causality by observational studies affects the inference of the findings. Secondly, some potential confounders, including lifestyle factors, were unavailable and thereby unaccounted for in this study, although matching by age and sex and adjustment with a comprehensive list of confounders were conducted. Thirdly, the benefits of the drugs in vaccinated patients stratified further by number of doses or by type of vaccine (inactivated versus mRNA) were not examined, and the possibility of a dose–response relationship of vaccine with drug-effectiveness observed in previous studies7, 8, 9, 10 could not be ascertained. However, benefits of reduced risks in the post-acute phase associated with subgroups of unvaccinated and vaccinated patients were similar, indicating effectiveness of drugs irrespective of vaccination status.
In conclusion, the findings of this study demonstrate the survival benefits of treatment with the COVID-19 oral antivirals, molnupiravir and nirmatrelvir–ritonavir, in reducing the risk of mortality in the post-acute phase in hospitalized patients, especially in older adults. These benefits are observed in both, vaccinated and unvaccinated patients. Moreover, treatment with nirmatrelvir–ritonavir may also be beneficial in lowering the likelihood of requiring hospitalization or A&E visits. Further study in larger cohorts (especially younger patients) is warranted.
Data availability
Data will not be made available to others because the data custodians have not given permission.
Funding
This work was supported by the Health and Medical Research Fund Research on COVID-19, The Hong Kong Special Administrative Region (HKSAR) Government (Principal Investigator (WP2): EWC; Ref No. COVID1903011); Collaborative Research Fund, University Grants Committee, the HKSAR Government (Principal Investigator: ICKW; Ref. No. C7154-20GF); and Research Grant from the Health Bureau, the HKSAR Government (Principal Investigator: ICKW; Ref. No. COVID19F01). ICKW and FTTL are partially supported by the Laboratory of Data Discovery for Health (D24H) funded by AIR@InnoHK administered by Innovation and Technology Commission.
Ethics 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).
Declaration of Competing Interest
EYFW has received research grants from the Food and Health Bureau of the Government of the Hong Kong Special Administrative Region, and the Hong Kong Research Grants Council, outside the submitted work. FTTL has been supported by the RGC Postdoctoral Fellowship under the Hong Kong Research Grants Council and has received research grants from the Food and Health Bureau of the Government of the Hong Kong Special Administrative Region, outside the submitted work. CSLC has received grants from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grant Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA, and Amgen; and personal fees from PrimeVigilance; outside the submitted work. XL has received research grants from the Food and Health Bureau of the Government of the Hong Kong Special Administrative Region; research and educational grants from Janssen and Pfizer; internal funding from the University of Hong Kong; and consultancy fees from Merck Sharp & Dohme; Dohme, unrelated to this work. CKHW has received research grants from the Food and Health Bureau of the Hong Kong Government, the Hong Kong Research Grants Council, and the EuroQol Research Foundation, unrelated to this work. IFNH received speaker fees from MSD. ICKW reports research funding from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong Research Grants Council, 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, outside the submitted work; and is a non-executive director of Jacobson Medical in Hong Kong and a consultant to IQVIA and World Health Organization. EWC reports grants from Research Grants Council (RGC, Hong Kong), 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, and Narcotics Division of the Security Bureau of the Hong Kong Special Administrative Region; honorarium from Hospital Authority; outside the submitted work. All other authors declare no competing interests.
Acknowledgment
We gratefully acknowledge the Department of Health and the Hospital Authority for facilitating data access.
Footnotes
Eric Yuk Fai Wan, Boyuan Wang, and Sukriti Mathur are co-first authors and contributed equally.
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jinf.2023.02.029.
Appendix A. Supplementary material
Supplementary material
.
References
- 1.Evans A., Qi C., Adebayo J.O., Underwood J., Coulson J., Bailey R., et al. Real-world effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab on preventing hospital admission among higher-risk patients with COVID-19 in Wales: a retrospective cohort study. J Infect. 2023 doi: 10.1016/j.jinf.2023.02.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Agarwal A., Rochwerg B., Lamontagne F., Siemieniuk R.A.C., Agoritsas T., Askie L., et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;370:m3379. doi: 10.1136/bmj.m3379. [DOI] [PubMed] [Google Scholar]
- 3.Ledford H. Long-COVID treatments: why the world is still waiting. Nature. 2022;608(7922):258–260. doi: 10.1038/d41586-022-02140-w. PubMed PMID: 35945375. Epub 2022/08/10. eng. [DOI] [PubMed] [Google Scholar]
- 4.Wan E.Y.F., Wang Y., Chui C.S.L., Mok A.H.Y., Xu W., Yan V.K.C., et al. Safety of an inactivated, whole-virion COVID-19 vaccine (CoronaVac) in people aged 60 years or older in Hong Kong: a modified self-controlled case series. Lancet Healthy Longev. 2022;3(7):e491–e500. doi: 10.1016/S2666-7568(22)00125-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Wan E.Y.F., Chui C.S.L., Lai F.T.T., Chan E.W.Y., Li X., Yan V.K.C., et al. Bell's palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study. Lancet Infect Dis. 2022;22(1):64–72. doi: 10.1016/S1473-3099(21)00451-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wan E.Y.F., Mok A.H.Y., Yan V.K.C., Wang B., Zhang R., Hong S.N., et al. Vaccine effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 Omicron BA.2 infection, hospitalisation, severe complications, cardiovascular disease and mortality in patients with diabetes mellitus: a case control study. J Infect. 2022;85(5):e140–e144. doi: 10.1016/j.jinf.2022.08.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Yan V.K.C., Wan E.Y.F., Ye X., Mok A.H.Y., Lai F.T.T., Chui C.S.L., et al. Effectiveness of BNT162b2 and CoronaVac vaccinations against mortality and severe complications after SARS-CoV-2 Omicron BA. 2 infection: a case-control study. Emerg Microbes Infect. 2022;11(1):2304–2314. doi: 10.1080/22221751.2022.2114854. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Wan E.Y.F., Mok A.H.Y., Yan V.K.C., Wang B., Zhang R., Hong S.N., et al. Vaccine effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 Omicron BA. 2 infection, hospitalisation, severe complications, cardiovascular disease and mortality in patients with diabetes mellitus: a case control study. J Infect. 2022;5:e140–e144. doi: 10.1016/j.jinf.2022.08.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Yip T.C.F., Lui G.C.Y., Lai M.S.M., Wong V.W.S., Tse Y.K., Ma B.H.M., et al. Impact of the use of oral antiviral agents on the risk of hospitalization in community coronavirus disease 2019 patients (COVID-19) Clin Infect Dis. 2022;76(3):e26–e33. doi: 10.1093/cid/ciac687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Wong C.K.H., Au I.C.H., Lau K.T.K., Lau E.H.Y., Cowling B.J., Leung G.M. Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study. Lancet. 2022;400(10359):1213–1222. doi: 10.1016/S0140-6736(22)01586-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material
Data Availability Statement
Data will not be made available to others because the data custodians have not given permission.