Clinical Outcomes Following Treatment for COVID-19 With Nirmatrelvir/Ritonavir and Molnupiravir Among Patients Living in Nursing Homes.

Importance: Older patients living in nursing homes are at very high risk of mortality after getting COVID-19. Objective: To evaluate outcomes following oral antiviral treatment for COVID-19 among nonhospitalized older patients living in nursing homes. Design, Setting, and Participants: This is a territory-wide, retrospective cohort study conducted between February 16 and March 31, 2022, with the last follow-up date on April 25, 2022. Participants were patients with COVID-19 living in nursing homes in Hong Kong. Data analysis was performed from May to June 2022. Exposures: Molnupiravir, nirmatrelvir/ritonavir, or no oral antiviral treatment. Main Outcomes and Measures: The primary outcome was hospitalization for COVID-19, and the secondary outcome was risk of inpatient disease progression (ie, admission to intensive care unit, use of invasive mechanical ventilation, and/or death). Results: Of 14 617 patients (mean [SD] age, 84.8 [10.2] years; 8222 women [56.2%]), 8939 (61.2%) did not use oral antivirals, 5195 (35.5%) used molnupiravir, and 483 (3.3%) used nirmatrelvir/ritonavir. Compared with patients who did not use oral antivirals, those who used molnupiravir and nirmatrelvir/ritonavir were more likely to be female and less likely to have comorbid illnesses and hospitalization in the past year. At a median (IQR) follow-up of 30 (30-30) days, 6223 patients (42.6%) were hospitalized and 2307 patients (15.8%) experienced inpatient disease progression. After propensity score weighting, both molnupiravir and nirmatrelvir/ritonavir were associated with a reduced risk of hospitalization (molnupiravir, weighted hazard ratio [wHR], 0.46; 95% CI, 0.37-0.57; P < .001; nirmatrelvir/ritonavir, wHR, 0.46; 95% CI, 0.32-0.65; P < .001) and inpatient disease progression (molnupiravir, wHR, 0.35; 95% CI, 0.23-0.51; P < .001; nirmatrelvir/ritonavir, wHR, 0.17; 95% CI, 0.06-0.44; P < .001). Nirmatrelvir/ritonavir was comparable to molnupiravir in achieving better clinical outcomes (hospitalization, wHR, 1.00; 95% CI, 0.75-1.33; P = .99; inpatient disease progression, wHR, 0.49; 95% CI, 0.20-1.20; P = .12). Conclusions and Relevance: In this retrospective cohort study, the use of oral antivirals to treat COVID-19 was associated with a reduced risk of hospitalization and inpatient disease progression among patients living in nursing homes. The findings of this study of nursing home residents could be reasonably extrapolated to other frail older patients living in the community.

Impact of the use of oral antiviral agents on the risk of hospitalization in community COVID-19 patients.

BACKGROUND: We examined the effectiveness of molnupiravir and nirmatrelvir/ritonavir in reducing hospitalization and deaths in a real-world cohort of non-hospitalized COVID-19 patients. METHODS: This was a territory-wide retrospective cohort study in Hong Kong. Non-hospitalized COVID-19 patients who attended designated outpatient clinics between 16 February and 31 March 2022 were identified. Patients hospitalized on the day of the first clinic appointment or used both oral antivirals were excluded. The primary endpoint was hospitalization. The secondary endpoint was a composite of intensive care unit admission, invasive mechanical ventilation use, and/or death. RESULTS: Of 93,883 patients, 83,154 (88.6%), 5,808 (6.2%), and 4,921 (5.2%) were oral antiviral non-users, molnupiravir users, and nirmatrelvir/ritonavir users respectively. Compared to non-users, oral antiviral users were older and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year. Molnupiravir users were older, and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year than nirmatrelvir/ritonavir users. At a median follow-up of 30 days, 1,931 (2.1%) patients were hospitalized and 225 (0.2%) patients developed the secondary endpoint. After propensity score weighting, nirmatrelvir/ritonavir use (weighted hazard ratio 0.79, 95%CI 0.65-0.95, P = 0.011) but not molnupiravir use (weighted hazard ratio 1.17, 95%CI 0.99-1.39, P = 0.062) was associated with a reduced risk of hospitalization than non-users. The use of molnupiravir or nirmatrelvir/ritonavir was not associated with a lower risk of the secondary endpoint as compared to non-users. CONCLUSION: Use of nirmatrelvir/ritonavir but not molnupiravir was associated with a reduced risk of hospitalization in real-world non-hospitalized COVID-19 patients.

Incidence of Viral Rebound After Treatment With Nirmatrelvir-Ritonavir and Molnupiravir.

Importance: Some patients treated with nirmatrelvir-ritonavir have experienced rebound of COVID-19 infections and symptoms; however, data are scarce on whether viral rebound also occurs in patients with COVID-19 receiving or not receiving molnupiravir. Objective: To examine the incidence of viral rebound in patients with COVID-19 who were treated with the oral antiviral agents nirmatrelvir-ritonavir and molnupiravir. Design, Setting, and Participants: This cohort study identified 41 255 patients with COVID-19 who were hospitalized from January 1, 2022, to March 31, 2022, in Hong Kong and assessed 12 629 patients with serial cycle threshold (Ct) values measured. Patients were followed up until the occurrence of the clinical end point of interest, death, date of data retrieval (July 31, 2022), or up to 30 days of follow-up, whichever came first. Exposures: Molnupiravir or nirmatrelvir-ritonavir treatment. Main Outcomes and Measures: Viral rebound, defined as a Ct value greater than 40 that decreased to 40 or less. Results: Of 12 629 patients (mean [SD] age, 65.4 [20.9] years; 6624 [52.5%] male), 11 688 (92.5%) were oral antiviral nonusers, 746 (5.9%) were molnupiravir users, and 195 (1.5%) were nirmatrelvir-ritonavir users. Compared with nonusers, oral antiviral users were older, had more comorbidities, and had lower complete vaccination rates. The mean (SD) baseline Ct value was slightly higher in nirmatrelvir-ritonavir users (22.2 [6.0]) than nonusers (21.0 [5.4]) and molnupiravir users (20.9 [5.4]) (P = .04). Viral rebound occurred in 68 nonusers (0.6%), 2 nirmatrelvir-ritonavir users (1.0%), and 6 molnupiravir users (0.8%). Among 76 patients with viral rebound, 12 of 68 nonusers, 1 of 6 molnupiravir users, and neither of the nirmatrelvir-ritonavir users died of COVID-19. Conclusions and Relevance: In this cohort study, viral rebound was uncommon in patients taking molnupiravir or nirmatrelvir-ritonavir and was not associated with increased risk of mortality. Given these findings, novel oral antivirals should be considered as a treatment for more patients with COVID-19 in the early phase of the infection.

Glucose-lowering drugs and outcome from COVID-19 among patients with type 2 diabetes mellitus: a population-wide analysis in Hong Kong.

OBJECTIVES: To investigate the association between baseline use of glucose-lowering drugs and serious clinical outcome among patients with type 2 diabetes. DESIGN: Territory-wide retrospective cohort of confirmed cases of COVID-19 between January 2020 and February 2021. SETTING: All public health facilities in Hong Kong. PARTICIPANTS: 1220 patients with diabetes who were admitted for confirmed COVID-19. PRIMARY AND SECONDARY OUTCOME MEASURES: Composite clinical endpoint of intensive care unit admission, requirement of invasive mechanical ventilation and/or in-hospital death. RESULTS: In this cohort (median age 65.3 years, 54.3% men), 737 (60.4%) patients were treated with metformin, 385 (31.6%) with sulphonylureas, 199 (16.3%) with dipeptidyl peptidase-4 (DPP-4) inhibitors and 273 (22.4%) with insulin prior to admission. In multivariate Cox regression, use of metformin and DPP-4 inhibitors was associated with reduced incidence of the composite endpoint relative to non-use, with respective HRs of 0.51 (95% CI 0.34 to 0.77, p=0.001) and 0.46 (95% CI 0.29 to 0.71, p<0.001), adjusted for age, sex, diabetes duration, glycated haemoglobin (HbA1c), smoking, comorbidities and drugs. Use of sulphonylureas (HR 1.55, 95% CI 1.07 to 2.24, p=0.022) and insulin (HR 6.34, 95% CI 3.72 to 10.78, p<0.001) were both associated with increased hazards of the composite endpoint. CONCLUSIONS: Users of metformin and DPP-4 inhibitors had fewer adverse outcomes from COVID-19 compared with non-users, whereas insulin and sulphonylurea might predict a worse prognosis.

Current and Past Infections of HBV Do Not Increase Mortality in Patients With COVID-19.

BACKGROUND AND AIMS: We compared risk of acute liver injury and mortality in patients with COVID-19 and current, past, and no HBV infection. APPROACH AND RESULTS: This was a territory-wide retrospective cohort study in Hong Kong. Patients with COVID-19 between January 23, 2020, and January 1, 2021, were identified. Patients with hepatitis C or no HBsAg results were excluded. The primary outcome was mortality. Acute liver injury was defined as alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal (ULN; i.e., 80 U/L), with total bilirubin ≥2 × ULN (i.e., 2.2 mg/dL) and/or international normalized ratio ≥1.7. Of 5,639 patients included, 353 (6.3%) and 359 (6.4%) had current and past HBV infection, respectively. Compared to patients without known HBV exposure, current HBV-infected patients were older and more likely to have cirrhosis. Past HBV-infected patients were the oldest, and more had diabetes and cardiovascular disease. At a median follow-up of 14 (9-20) days, 138 (2.4%) patients died; acute liver injury occurred in 58 (1.2%), 8 (2.3%), and 11 (3.1%) patients with no, current, and past HBV infection, respectively. Acute liver injury (adjusted HR [aHR], 2.45; 95% CI, 1.52-3.96; P < 0.001), but not current (aHR, 1.29; 95% CI, 0.61-2.70; P = 0.507) or past (aHR, 0.90; 95% CI, 0.56-1.46; P = 0.681) HBV infection, was associated with mortality. Use of corticosteroid, antifungal, ribavirin, or lopinavir-ritonavir (adjusted OR [aOR], 2.55-5.63), but not current (aOR, 1.93; 95% CI, 0.88-4.24; P = 0.102) or past (aOR, 1.25; 95% CI, 0.62-2.55; P = 0.533) HBV infection, was associated with acute liver injury. CONCLUSION: Current or past HBV infections were not associated with more liver injury and mortality in COVID-19.

SARS-CoV-2 Viral Persistence Based on Cycle Threshold Value and Liver Injury in Patients With COVID-19.

BACKGROUND: Liver injury in patients with coronavirus disease 2019 (COVID-19) is common and prognostic. Direct viral tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for angiotensin-converting enzyme 2 receptors in hepatocytes may be one of the mechanisms of liver injury. We aimed to determine the role of viral persistence of SARS-CoV-2, based on cycle threshold (Ct) value, in liver injury in COVID-19. METHODS: This was a territory-wide retrospective cohort study of all public hospitals in Hong Kong. Laboratory-confirmed COVID-19 was identified. Serial liver biochemistries and Ct values of SARS-CoV-2 RNA were analyzed. RESULTS: We identified 7622 COVID-19 patients (mean age, 47 years; 48.2% male) diagnosed from March 24 to January 1, 2021, who had serial liver biochemistries and Ct values. A total of 1363 (17.9%) COVID-19 patients had alanine transferase (ALT)/aspartate aminotransferase (AST) elevations with 2 temporal patterns-early (within first 14 days of symptom onset) and late (>14 days from symptom onset). COVID-19 patients with ALT/AST elevations had a lower Ct value at admission (23 vs 25; P < .001), day 5 (24 vs 26; P < .001), and day 20 (31 vs 32; P < .001) after admission, compared with those without ALT/AST elevations. COVID-19 patients with ALT/AST elevations had a longer duration from first positive to first negative reverse transcription polymerase chain reaction test for SARS-CoV-2 (13 vs 9 days; P < .001). ALT/AST elevation and presence of diabetes were independent risk factors of viral persistence. CONCLUSIONS: Liver injury in COVID-19 is linked to a higher SARS-CoV-2 viral load during the early phase of infection, signifying a possible direct viral injury to the liver. Prolonged viral persistence of SARS-CoV-2 is associated with liver injury.

Risks of AKI and Major Adverse Clinical Outcomes in Patients with Severe Acute Respiratory Syndrome or Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) are closely related. The effect of AKI on the clinical outcomes of these two conditions is unclear. METHODS: This retrospective, territory-wide cohort study used an electronic public healthcare database in Hong Kong to identify patients with SARS or COVID-19 by diagnosis codes, virologic results, or both. The primary endpoint was a composite of intensive care unit admission, use of invasive mechanical ventilation, and/or death. RESULTS: We identified 1670 patients with SARS and 1040 patients with COVID-19 (median ages, 41 versus 35 years, respectively). Among patients with SARS, 26% met the primary endpoint versus 5.3% of those with COVID-19. Diabetes mellitus, abnormal liver function, and AKI were factors significantly associated with the primary endpoint among patients with either SARS or COVID-19. Among patients with SARS, 7.9%, 2.1%, and 3.7% developed stage 1, stage 2, and stage 3 AKI, respectively; among those with COVID-19, 6.6%, 0.4%, and 1.1% developed stage 1, stage 2, and stage 3 AKI, respectively. In both groups, factors significantly associated with AKI included diabetes mellitus and hypertension. Among patients with AKI, those with COVID-19 had a lower rate of major adverse clinical outcomes versus patients with SARS. Renal function recovery usually occurred within 30 days after an initial AKI event. CONCLUSIONS: AKI rates were higher among patients with SARS than those with COVID-19. AKI was associated with major adverse clinical outcomes for both diseases. Patients with diabetes mellitus and abnormal liver function were also at risk of developing severe consequences after SARS and COVID-19 infection.

Significantly Lower Case-fatality Ratio of Coronavirus Disease 2019 (COVID-19) than Severe Acute Respiratory Syndrome (SARS) in Hong Kong-A Territory-Wide Cohort Study.

BACKGROUND: The case-fatality ratios (CFR) of coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) appeared to differ substantially. We aimed to compare the CFR and its predictors of COVID-19 and SARS patients using a territory-wide cohort in Hong Kong. METHODS: This was a territory-wide retrospective cohort study using data captured from all public hospitals in Hong Kong. Laboratory-confirmed COVID-19 and SARS patients were identified. The primary endpoint was a composite endpoint of intensive care unit admission, use of mechanical ventilation, and/or death. RESULTS: We identified 1013 COVID-19 patients (mean age, 38.4 years; 53.9% male) diagnosed from 23 January to 14 April 2020 and 1670 SARS patients (mean age, 44.4 years; 44.0% male) from March to June 2003. Fifty-five (5.4%) COVID-19 patients and 432 (25.9%) SARS patients had reached the primary endpoint in 30 days. By 30 June 2003, 286 SARS patients had died (CFR, 17.1%). By 7 June 2020, 4 COVID-19 patients had died (CFR, 0.4%). After adjusting for demographic and clinical parameters, COVID-19 was associated with a 71% lower risk of primary endpoint compared with SARS (adjusted hazard ratio, 0.29; 95% confidence interval, .21-.40; P < .0001). Age, diabetes mellitus, and laboratory parameters (high lactate dehydrogenase, high C-reactive protein, and low platelet count) were independent predictors of the primary endpoint in COVID-19 patients, whereas use of antiviral treatments was not associated with primary endpoint. CONCLUSIONS: The CFR of COVID-19 was 0.4%. Age and diabetes were associated with worse outcomes, whereas antiviral treatments were not.

Liver injury is independently associated with adverse clinical outcomes in patients with COVID-19.

OBJECTIVE: Data on serial liver biochemistries of patients infected by different human coronaviruses (HCoVs) are lacking. The impact of liver injury on adverse clinical outcomes in coronavirus disease 2019 (COVID-19) patients remains unclear. DESIGN: This was a retrospective cohort study using data from a territory-wide database in Hong Kong. COVID-19, severe acute respiratory syndrome (SARS) and other HCoV patients were identified by diagnosis codes and/or virological results. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation was defined as ALT/AST ≥2 × upper limit of normal (ie, 80 U/L). The primary end point was a composite of intensive care unit (ICU) admission, use of invasive mechanical ventilation and/or death. RESULTS: We identified 1040 COVID-19 patients (mean age 38 years, 54% men), 1670 SARS patients (mean age 44 years, 44% men) and 675 other HCoV patients (mean age 20 years, 57% men). ALT/AST elevation occurred in 50.3% SARS patients, 22.5% COVID-19 patients and 36.0% other HCoV patients. For COVID-19 patients, 53 (5.1%) were admitted to ICU, 22 (2.1%) received invasive mechanical ventilation and 4 (0.4%) died. ALT/AST elevation was independently associated with primary end point (adjusted OR (aOR) 7.92, 95% CI 4.14 to 15.14, p<0.001) after adjusted for albumin, diabetes and hypertension. Use of lopinavir-ritonavir ±ribavirin + interferon beta (aOR 1.94, 95% CI 1.20 to 3.13, p=0.006) and corticosteroids (aOR 3.92, 95% CI 2.14 to 7.16, p<0.001) was independently associated with ALT/AST elevation. CONCLUSION: ALT/AST elevation was common and independently associated with adverse clinical outcomes in COVID-19 patients. Use of lopinavir-ritonavir, with or without ribavirin, interferon beta and/or corticosteroids was independently associated with ALT/AST elevation.

Management of patients with liver derangement during the COVID-19 pandemic: an Asia-Pacific position statement.

The COVID-19 pandemic has spread rapidly worldwide. It is common to encounter patients with COVID-19 with abnormal liver function, either in the form of hepatitis, cholestasis, or both. The clinical implications of liver derangement might be variable in different clinical scenarios. With growing evidence of its clinical significance, it would be clinically helpful to provide practice recommendations for various common clinical scenarios of liver derangement during the COVID-19 pandemic. The Asia-Pacific Working Group for Liver Derangement during the COVID-19 Pandemic was formed to systematically review the literature with special focus on the clinical management of patients who have been or who are at risk of developing liver derangement during this pandemic. Clinical scenarios covering the use of pharmacological treatment for COVID-19 in the case of liver derangement, and assessment and management of patients with chronic hepatitis B or hepatitis C, non-alcoholic fatty liver disease, liver cirrhosis, and liver transplantation during the pandemic are discussed.