Reports of symptomatic rebound and/or test re-positivity among COVID-19 patients following the standard five-day treatment course of nirmatrelvir/ritonavir have sparked debates regarding optimal ...treatment timing and dosage. It is unclear whether initiating nirmatrelvir/ritonavir immediately after symptom onset would improve clinical outcomes and/or lead to post-treatment viral burden rebound due to inadequate viral clearance during treatment. Here we show that, by emulating a randomized target trial using real-world electronic medical record data from all 87,070 adult users of nirmatrelvir/ritonavir in Hong Kong between 16th March 2022 and 15th January 2023, early initiation of nirmatrelvir/ritonavir treatment (0 to 1 days after symptom onset or diagnosis) significantly reduced the incidence of 28-day all-cause mortality and hospitalization compared to delayed initiation (2 or more days) (absolute risk reduction ARR: 1.50% (95% confidence interval 1.17-1.80%); relative risk RR: 0.77 (0.73, 0.82)), but may be associated with a significant elevated risk of viral burden rebound (ARR: -1.08% (-1.55%, -0.46%)), although the latter estimates were associated with high uncertainty due to limited sample sizes. As such, patients should continue to initiate nirmatrelvir/ritonavir early after symptom onset or diagnosis to better protect against the more serious outcomes of hospitalization and mortality.
Little is known about the real-world effectiveness of oral antivirals against the SARS-CoV-2 omicron (B.1.1.529) variant. We aimed to assess the clinical effectiveness of two oral antiviral drugs ...among community-dwelling COVID-19 outpatients in Hong Kong.
In this observational study, we used data from the Hong Kong Hospital Authority to identify an unselected, territory-wide cohort of non-hospitalised patients with an officially registered diagnosis of SARS-CoV-2 infection between Feb 26 and June 26, 2022, during the period in which the omicron subvariant BA.2.2 was dominant in Hong Kong. We used a retrospective cohort design as primary analysis, and a case-control design as sensitivity analysis. We identified patients with COVID-19 who received either molnupiravir (800 mg twice daily for 5 days) or nirmatrelvir plus ritonavir (nirmatrelvir 300 mg and ritonavir 100 mg twice daily for 5 days, or nirmatrelvir 150 mg and ritonavir 100 mg if estimated glomerular filtration rate was 30–59 mL/min per 1·73 m2). Outpatient oral antiviral users were matched with controls using propensity score (1:10) according to age, sex, date of SARS-CoV-2 infection diagnosis, Charlson Comorbidity Index score, and vaccination status. Study outcomes were death, COVID-19-related hospitalisation, and in-hospital disease progression (in-hospital death, invasive mechanical ventilation, or intensive care unit admission). Hazard ratios (HRs) were estimated by Cox regression for the primary analysis, and odds ratios in oral antiviral users compared with non-users by logistic regression for the sensitivity analysis.
Among 1 074 856 non-hospitalised patients with COVID-19, 5383 received molnupiravir and 6464 received nirmatrelvir plus ritonavir in the community setting. Patients were followed up for a median of 103 days in the molnupiravir group and 99 days in the nirmatrelvir plus ritonavir group. Compared with nirmatrelvir plus ritonavir users, those on molnupiravir were older (4758 85·9% vs 4418 88.7% aged >60 years) and less likely to have been fully vaccinated (1850 33·4% vs 800 16·1%). Molnupiravir use was associated with lower risks of death (HR 0·76 95% CI 0·61–0·95) and in-hospital disease progression (0·57 0·43–0·76) than non-use was, whereas risk of hospitalisation was similar in both groups (0·98 0·89–1·06). Nirmatrelvir plus ritonavir use was associated with lower risks of death (0·34 0·22–0·52), hospitalisation (0·76 0·67–0·86), and in-hospital disease progression (0·57 0·38–0·87) than non-use was. We consistently found reduced risks of mortality and hospitalisation associated with early oral antiviral use among older patients. The findings from the case-control analysis broadly supported those from the primary analysis.
During Hong Kong's wave of SARS-CoV-2 omicron subvariant BA.2.2, among non-hospitalised patients with COVID-19, early initiation of novel oral antivirals was associated with reduced risks of mortality and in-hospital disease progression. Nirmatrelvir plus ritonavir use was additionally associated with a reduced risk of hospitalisation.
Health and Medical Research Fund, Health Bureau, Government of Hong Kong Special Administrative Region, China.
For the Chinese translation of the abstract see Supplementary Materials section.
Data on the effectiveness of oral antivirals in patients with mild-to-moderate COVID-19 are urgently needed. This retrospective cohort study aimed to evaluate the clinical and virological outcomes ...associated with molnupiravir or nirmatrelvir–ritonavir use in hospitalised patients with mild-to-moderate COVID-19 during a pandemic wave dominated by the omicron BA.2 subvariant.
We analysed data from a territory-wide retrospective cohort of patients in Hong Kong who were hospitalised with a confirmed diagnosis of SARS-CoV-2 infection between Feb 26 and April 26, 2022. Data were extracted from the Hospital Authority, the Department of Health, and the Hong Kong Death Registry. Patients were eligible for inclusion if their admission date was within 3 days before or after confirmation of their COVID-19 diagnosis. Those who were admitted to hospital more than 5 days after symptom onset, were younger than 18 years, had a history of oral antiviral use before admission, required supplemental oxygen on admission, had drug-related contraindications to nirmatrelvir–ritonavir use, or had severe renal or severe liver impairment were excluded. Patients who received the oral antivirals molnupiravir or nirmatrelvir–ritonavir were matched with controls using propensity-score matching in a ratio of 1:1. The primary outcome was all-cause mortality and secondary outcomes included a composite outcome of disease progression (all-cause mortality, initiation of invasive mechanical ventilation IMV, intensive care unit ICU admission, or the need for oxygen therapy) and each of these individual disease progression outcomes, and time to reaching a low viral burden (RT-PCR cycle threshold value ≥30). For each event outcome, crude incidence rates were calculated and hazard ratios (HRs) estimated using Cox regression models.
We identified 40 776 patients hospitalised with SARS-CoV-2 infection during the study period, with a mean follow-up of 41·3 days (total 925 713 person-days). After exclusions and propensity-score matching, we included 1856 molnupiravir recipients and 1856 matched controls, and 890 nirmatrelvir-ritonavir recipients and 890 matched controls. A lower risk of all-cause mortality was observed in molnupiravir recipients (crude incidence rate per 10 000 person-days 19·98 events 95% CI 16·91–23·45) versus matched controls (38·07 events 33·85–42·67; HR 0·48 95% CI 0·40–0·59, p<0·0001) and in nirmatrelvir–ritonavir recipients (10·28 events 7·03–14·51) versus matched controls (26·47 events 21·34–32·46; HR 0·34 0·23–0·50, p<0·0001). Oral antiviral recipients also had lower risks of the composite disease progression outcome (molnupiravir HR 0·60 95% CI 0·52–0·69, p<0·0001; nirmatrelvir–ritonavir 0·57 0·45–0·72, p<0·0001) and need for oxygen therapy (molnupiravir 0·69 0·57–0·83, p=0·0001; nirmatrelvir–ritonavir 0·73 0·54–0·97, p=0·032) compared with controls. Time to achieving a low viral burden was significantly shorter among oral antiviral recipients than matched controls (molnupiravir HR 1·38 95% CI 1·15–1·64, p=0·0005; nirmatrelvir–ritonavir 1·38 1·07–1·79, p=0·013). Significant differences in initiation of IMV and ICU admission were not found.
During a wave of SARS-CoV-2 omicron BA.2, initiation of novel oral antiviral treatments in hospitalised patients not requiring oxygen therapy on admission showed substantial clinical benefit. Our findings support the early use of oral antivirals in this population of patients.
Health and Medical Research Fund (Health Bureau, Government of the Hong Kong Special Administrative Region).
For the Chinese translation of the abstract see Supplementary Materials section.
Abstract Currently there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in paediatric patients with SARS-CoV-2 infection. This target trial emulation ...study aims to address this gap by evaluating the use of nirmatrelvir/ritonavir in non-hospitalized paediatric patients aged 12–17 years with SARS-CoV-2 Omicron variant infection. Among paediatric patients diagnosed between 16th March 2022 and 5th February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or COVID-19 diagnosis. Primary outcome was 28 day all-cause mortality or all-cause hospitalization, while secondary outcomes were 28 day in-hospital disease progression, 28 day COVID-19-specific hospitalization, multisystem inflammatory syndrome in children (MIS-C), acute liver injury, acute renal failure, and acute respiratory distress syndrome. Overall, 49,378 eligible paediatric patients were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28 day all-cause hospitalization (absolute risk reduction = 0.23%, 95%CI = 0.19%–0.31%; relative risk = 0.66, 95%CI = 0.56–0.71). No events of mortality, in-hospital disease progression, or adverse clinical outcomes were observed among nirmatrelvir/ritonavir users. The findings confirmed the effectiveness of nirmatrelvir/ritonavir in reducing all-cause hospitalization risk among non-hospitalized pediatric patients with SARS-CoV-2 Omicron variant infection.
Viral rebound after nirmatrelvir–ritonavir treatment has implications for the clinical management and isolation of patients with COVID-19. We evaluated an unselected, population-wide cohort to ...identify the incidence of viral burden rebound and associated risk factors and clinical outcomes.
We did a retrospective cohort study of hospitalised patients with a confirmed diagnosis of COVID-19 in Hong Kong, China, for an observation period from Feb 26 to July 3, 2022 (during the omicron BA.2.2 variant wave). Adult patients (age ≥18 years) admitted 3 days before or after a positive COVID-19 test were selected from medical records held by the Hospital Authority of Hong Kong. We included patients with non-oxygen-dependent COVID-19 at baseline receiving either molnupiravir (800 mg twice a day for 5 days), nirmatrelvir–ritonavir (nirmatrelvir 300 mg with ritonavir 100 mg twice a day for 5 days), or no oral antiviral treatment (control group). Viral burden rebound was defined as a reduction in cycle threshold (Ct) value (≥3) on quantitative RT-PCR test between two consecutive measurements, with such decrease sustained in an immediately subsequent Ct measurement (for those patients with ≥3 Ct measurements). Logistic regression models were used to identify prognostic factors for viral burden rebound, and to assess associations between viral burden rebound and a composite clinical outcome of mortality, intensive care unit admission, and invasive mechanical ventilation initiation, stratified by treatment group.
We included 4592 hospitalised patients with non-oxygen-dependent COVID-19 (1998 43·5% women and 2594 56·5% men). During the omicron BA.2.2 wave, viral burden rebound occurred in 16 of 242 patients (6·6% 95% CI 4·1–10·5) receiving nirmatrelvir–ritonavir, 27 of 563 (4·8% 3·3–6·9) receiving molnupiravir, and 170 of 3787 (4·5% 3·9–5·2) in the control group. The incidence of viral burden rebound did not differ significantly across the three groups. Immunocompromised status was associated with increased odds of viral burden rebound, regardless of antiviral treatment (nirmatrelvir–ritonavir: odds ratio OR 7·37 95% CI 2·56–21·26, p=0·0002; molnupiravir: 3·05 1·28–7·25, p=0·012; control: 2·21 1·50–3·27, p<0·0001). Among patients receiving nirmatrelvir–ritonavir, the odds of viral burden rebound were higher in those aged 18–65 years (vs >65 years; 3·09 1·00–9·53, p=0·050), those with high comorbidity burden (score >6 on the Charlson Comorbidity Index; 6·02 2·09–17·38, p=0·0009), and those concomitantly taking corticosteroids (7·51 1·67–33·82, p=0·0086); whereas the odds were lower in those who were not fully vaccinated (0·16 0·04–0·67, p=0·012). In patients receiving molnupiravir, those aged 18–65 years (2·68 1·09–6·58, p=0·032) or on concomitant corticosteroids (3·11 1·23–7·82, p=0·016) had increased odds of viral burden rebound. We found no association between viral burden rebound and occurrence of the composite clinical outcome from day 5 of follow-up (nirmatrelvir–ritonavir: adjusted OR 1·90 0·48–7·59, p=0·36; molnupiravir: 1·05 0·39–2·84, p=0·92; control: 1·27 0·89–1·80, p=0·18).
Viral burden rebound rates are similar between patients with antiviral treatment and those without. Importantly, viral burden rebound was not associated with adverse clinical outcomes.
Health and Medical Research Fund, Health Bureau, The Government of the Hong Kong Special Administrative Region, China.
For the Chinese translation of the abstract see Supplementary Materials section.
To date, there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected pregnant persons. ...This target trial emulation study aimed to address this gap by evaluating the use of nirmatrelvir/ritonavir in nonhospitalized pregnant women with symptomatic SARS-CoV-2 Omicron variant infection. Among patients diagnosed between 16 March 2022 and 5 February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or coronavirus disease 2019 (COVID-19) diagnosis. Primary outcomes were maternal morbidity and mortality index (MMMI), all-cause maternal death and COVID-19-related hospitalization, while secondary outcomes were individual components of MMMI, preterm birth, stillbirth, neonatal death and cesarean section. One-to-ten propensity-score matching was conducted between nirmatrelvir/ritonavir users and nonusers, followed by cloning, censoring and weighting. Overall, 211 pregnant women on nirmatrelvir/ritonavir and 1,998 nonusers were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28-day MMMI risk (absolute risk reduction (ARR) = 1.47%, 95% confidence interval (CI) = 0.21-2.34%) but not 28-days COVID-19-related hospitalization (ARR = -0.09%, 95% CI = -1.08% to 0.71%). Nirmatrelvir/ritonavir treatment was also associated with reduced risks of cesarean section (ARR = 1.58%, 95% CI = 0.85-2.39%) and preterm birth (ARR = 2.70%, 95% CI = 0.98-5.31%). No events of maternal or neonatal death or stillbirth were recorded. The findings suggest that nirmatrelvir/ritonavir is an effective treatment in symptomatic pregnant women with SARS-CoV-2 Omicron variant infection.
There was initially insufficient understanding regarding suitable pharmacological treatment for pediatric Coronavirus Disease 2019 (COVID-19) patients. Lopinavir-ritonavir (LPV/r) was originally used ...for the treatment of Human Immunodeficiency Virus-1 (HIV-1) infection. It was also used in patients with severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) with positive results. Nonetheless, results from recent randomized controlled trials and observational studies on COVID-19 patients were unfavorable. We sought to evaluate the clinical outcomes associated with early treatment with LPV/r for pediatric COVID-19 patients.
A total of 933 COVID-19 patients aged ≤ 18 years were admitted between 21 January 2020 and 31 January 2021 in Hong Kong. Exposure was receiving LPV/r within the first two days of admission. Time to clinical improvement, hospital discharge, seroconversion and hyperinflammatory syndrome, cumulative costs, and hospital length of stay were assessed. Multivariable Cox proportional hazard and linear models were performed to estimate hazard ratios (HR) and their 95% confidence intervals (CI) of time-to-event and continuous outcomes, respectively.
LPV/r users were associated with longer time to clinical improvement (HR 0.51, 95% CI 0.38-0.70; p < 0.001), hospital discharge (HR 0.51, 95% CI 0.38-0.70; p < 0.001) and seroconversion (HR 0.59, 95% CI 0.43-0.80; p < 0.001) when compared with controls. LPV/r users were also associated with prolonged hospital length of stay (6.99 days, 95% CI 6.23-7.76; p < 0.001) and higher costs at 30 days (US$11,709 vs US$8270; p < 0.001) as opposed to controls.
Early treatment with LPV/r for pediatric COVID-19 patients was associated with longer time to clinical improvement. Our study advocates the recommendation against LPV/r use for pediatric patients across age groups.
Abstract
Background
Evidence remains inconclusive on any significant benefits of remdesivir in patients with mild-to-moderate COVID-19. This study explored the disease progression, various clinical ...outcomes, changes in viral load, and costs associated with early remdesivir treatment among COVID-19 patients.
Methods
A territory-wide retrospective cohort of 10 419 patients with COVID-19 hospitalized from 21 January 2020 to 31 January 2021 in Hong Kong was identified. Early remdesivir users were matched with controls using propensity-score matching in a ratio ≤1:4. Study outcomes were time to clinical improvement of at least 1 point on WHO clinical progression scale, hospital discharge, recovery, viral clearance, low viral load, positive IgG antibody, in-hospital death, and composite outcomes of in-hospital death requiring invasive ventilation or intensive care.
Results
After multiple imputation and propensity-score matching, median follow-up was 14 days for both remdesivir (n = 352) and control (n = 1347) groups. Time to clinical improvement was significantly shorter in the remdesivir group than that of control (HR: 1.14; 95% CI: 1.01–1.29; P = .038), as well as for achieving low viral load (1.51; 1.24–1.83; P < .001) and positive IgG antibody (1.50; 1.31–1.70; P < .001). Early remdesivir treatment was associated with lower risk of in-hospital death (HR: .58; 95% CI: .34–.99; P = .045), in addition to a significantly shorter length of hospital stay (difference: −2.56 days; 95% CI: −4.86 to −.26; P = .029), without increasing risks of composite outcomes for clinical deterioration.
Conclusions
Early remdesivir treatment could be extended to hospitalized patients with moderate COVID-19 not requiring oxygen therapy on admission.
Among hospitalized patients with moderate COVID-19, early initiation of remdesivir was associated with significantly shorter time to clinical improvement, low viral load and positive IgG (immunoglobulin G) antibody, a shorter length of hospital stay, and a significantly lower risk of in-hospital death.
Abstract
Background
Evidence is lacking about any additional benefits of introducing remdesivir on top of dexamethasone, and the optimal timing of initiation.
Methods
In a territory-wide cohort of 10 ...445 coronavirus disease 2019 (COVID-19) patients from Hong Kong who were hospitalized between 21 January 2020 and 31 January 2021, 1544 had received dexamethasone during hospitalization. The exposure group consisted of patients who had initiated remdesivir prior to dexamethasone (n = 93) or co-initiated the 2 drugs simultaneously (n = 373), whereas the nonexposure group included patients who were given remdesivir after dexamethasone (n = 149) or those without remdesivir use (n = 929). Multiple imputation and inverse probability of treatment weighting for propensity score were applied and hazard ratios (HRs) of event outcomes were estimated using Cox regression models.
Results
Time to clinical improvement (HR = 1.23; 95% CI, 1.02–1.49; P = .032) and positive IgG antibody (HR = 1.22; 95% CI, 1.02–1.46; P = .029) were significantly shorter in the exposure group than that of nonexposure. The exposure group had a shorter hospital length of stay by 2.65 days among survivors, lower WHO clinical progression scale scores from 5 days of follow-up onwards, and lower risks of in-hospital death (HR = .59; 95% CI, .36–.98; P = .042) and composite outcomes; and without experiencing an increased risk of acute respiratory distress syndrome. Differences in the cumulative direct medical costs between groups were no longer significant from 17 days of follow-up onwards.
Conclusions
Initiation of remdesivir prior to or simultaneously with dexamethasone was associated with significantly shorter time to clinical improvement and positive IgG antibody, lower risk of in-hospital death, in addition to shorter length of hospital stay in patients with moderate COVID-19.
Initiation of remdesivir prior to or simultaneously with dexamethasone was associated with significantly shorter time to clinical improvement and positive IgG antibody, lower risk of death, in addition to a shorter length of hospital stay in patients with moderate COVID-19.
Objectives
The aim of this study is to quantify the mortality rate, direct healthcare costs, and cumulative life costs of pediatric patients with spinal muscular atrophy (SMA) type 1, type 2, and ...type 3 born in Hong Kong.
Methods
Data were collected from genetically confirmed SMA patients born in or after 2000 from the Hospital Authority medical database. Patients were followed up from birth until they died, left Hong Kong, reached 18 years, or initiated disease-modifying treatment. Study outcomes included incidence risks of mortality, cumulative direct medical costs—attendances of special outpatient clinics, emergency department, allied health services, and mean length of stay in hospitals over time. Total direct medical costs were calculated as unit costs multiplied by utilization frequencies of corresponding healthcare services at each age.
Results
Seventy-one patients with SMA were included. Over a median follow-up period of 6 years, the overall incidence rate of death was 5.422/100 person-years (95%CI 3.542–7.945/100 person-years). 67.7% and 11% of deaths occurred in SMA1 and SMA2 groups, respectively. The median age of death was 0.8 years in SMA1 and 10.9 years in SMA2. The mean cumulative direct medical costs in overall SMA, SMA1, SMA2 and SMA3 groups per patient were US$935,570, US$2,393,250, US$413,165, and US$40,735, respectively.
Interpretation: Our results confirmed a significantly raised mortality and extremely high healthcare burden for patients with SMA especially SMA type 1 and 2 without disease-modifying treatment. Study evaluating health and economic impact of newborn screening and early treatment is needed.
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