Cost-effectiveness of COVID-19 vaccination: A systematic review.

OBJECTIVE: The COVID-19 vaccination strategy has been widely used to protect population health worldwide. This study aims to summarize the cost-effectiveness evidence of economic evaluation of COVID-19 vaccination strategies to provide evidence supporting the usage of COVID-19 vaccination, especially where the supply of COVID-19 vaccine is limited. METHODS: A systematic literature review was performed by searching both English and Chinese databases, including PubMed, Embase, Science Direct, Web of Science, Medline, Scopus, and CNKI. Articles published from January 1, 2020 to August 1, 2022 (PROSPERO registration number: CRD42022355442). RESULTS: Of the 1035 papers identified, a total of 28 English studies that met the preset criteria were included. COVID-19 vaccination and booster vaccination were cost-effective or cost-saving regardless of the vaccine type; vaccine efficacy, vaccine price, vaccine supply or prioritization, and vaccination pace were the influential factors of cost-effectiveness among different population groups. When supply is adequate, mass vaccination should be encouraged, while when supply is inadequate, prioritizing the high risk and the elderly is more cost-effective. CONCLUSIONS: COVID-19 vaccination strategies are economically favorable in a wide range of countries and population groups, and further research on suitable strategies for booster COVID-19 vaccination is needed.

Impact of the COVID-19 Pandemic on Outpatient Service in Primary Healthcare Institutions: An Inspiration From Yinchuan of China.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has posed a great challenge to the healthcare system. This study evaluated the impact of the pandemic on the utilization of primary healthcare (PHC). METHODS: The outpatient data from 158 PHC institutions in Yinchuan from May 1, 2017 to April 30, 2020 were used. The difference in difference (DID) model was used to analyze the difference in the number of outpatient visits per day, total outpatient expenditure per day, and outpatient expenditure per visit between December 2019 and February 2020 compared with the same periods in two previous years. The autoregressive integrated moving average (ARIMA) modelling was used to investigate the association between the outpatient volume and the number of the last week's new COVID-19 cases in Yinchuan, Ningxia, and China. RESULTS: From December 2019 to February 2020, the decline in the number of outpatient visits per day (DID: -367.21 times, P=.004) was larger than that in two previous years, and a similar trend can be seen in the outpatient expenditure per day. However, the rise in the outpatient expenditure per visit (DID: 19.06 thousand yuan, P=.003) was larger than that in two previous years. In 2020, the outpatient visits for most types of diseases decreased from week 3 and rebounded after week 5. The decline and rebound of outpatient visits in the population aged 45 years and older were steeper than in those younger. The outpatient volume was negatively associated with the number of the last week's new COVID-19 cases. CONCLUSION: This study indicated a significant impact of the pandemic on PHC service utilization. Since PHC service is the foundation of the healthcare system in most developing countries, measures should be taken to make PHC help cope with the crisis and relieve the burden of hospital care.

COVID-19 pharmacological research trends: a bibliometric analysis.

Background: The coronavirus disease 2019 (COVID-19) pandemic is ravaging the world. Many therapies have been explored to treat COVID-19. This report aimed to assess the global research trends for the development of COVID-19 therapies. Methods: We searched the relevant articles on COVID-19 therapies published from January 1, 2020, to May 25, 2022, in the Web of Science Core Collection Database (WOSCC). VOSviewer 1.6.18 software was used to assess data on the countries, institutions, authors, collaborations, keywords, and journals that were most implicated in COVID-19 pharmacological research. The latest research and changing trends in COVID-19-relevant pharmacological research were analyzed. Results: After manually eliminating articles that do not meet the requirements, a total of 5,289 studies authored by 32,932 researchers were eventually included in the analyses, which comprised 95 randomized controlled trials. 3044 (57.6%) studies were published in 2021. The USA conducted the greatest number of studies, followed by China and India. The primary USA collaborators were China and England. The topics covered in the publications included: the general characteristics, the impact on pharmacists' work, the pharmacological research, broad-spectrum antiviral drug therapy and research, and promising targets or preventive measures, such as vaccine. The temporal diagram revealed that the current research hotspots focused on the vaccine, molecular docking, Mpro, and drug delivery keywords. Conclusion: Comprehensive bibliometric analysis can aid the rapid identification of the principal research topics, potential collaborators, and the direction of future research. Pharmacological research is critical for the development of therapeutic and preventive COVID-19-associated measures. This study may therefore provide valuable information for eradicating COVID-19.

Immunogenicity and reactogenicity of heterologous immunization schedules with COVID-19 vaccines: a systematic review and network meta-analysis.

BACKGROUND: Data on the immunogenicity and safety of heterologous immunization schedules are inconsistent. This study aimed to evaluate the immunogenicity and safety of homologous and heterologous immunization schedules. METHODS: Multiple databases with relevant studies were searched with an end date of October 31, 2021, and a website including a series of Coronavirus disease 2019 studies was examined for studies before March 31, 2022. Randomized controlled trials (RCTs) that compared different heterologous and homologous regimens among adults that reported immunogenicity and safety outcomes were reviewed. Primary outcomes included neutralizing antibodies against the original strain and serious adverse events (SAEs). A network meta-analysis (NMA) was conducted using a random-effects model. RESULTS: In all, 11 RCTs were included in the systematic review, and nine were ultimately included in the NMA. Among participants who received two doses of CoronaVac, another dose of mRNA or a non-replicating viral vector vaccine resulted in a significantly higher level of neutralizing antibody than a third CoronaVac 600 sino unit (SU); a dose of BNT162b2 induced the highest geometric mean ratio (GMR) of 15.24, 95% confidence interval [CI]: 9.53-24.39. Following one dose of BNT162b2 vaccination, a dose of mRNA-1273 generated a significantly higher level of neutralizing antibody than BNT162b2 alone (GMR = 1.32; 95% CI: 1.06-1.64), NVX-CoV2373 (GMR = 1.60; 95% CI: 1.16-2.21), or ChAdOx1 (GMR = 1.80; 95% CI: 1.25-2.59). Following one dose of ChAdOx1, a dose of mRNA-1273 was also more effective for improving antibody levels than ChAdOx1 (GMR = 11.09; 95% CI: 8.36-14.71) or NVX-CoV2373 (GMR = 2.87; 95% CI: 1.08-3.91). No significant difference in the risk for SAEs was found in any comparisons. CONCLUSIONS: Relative to vaccination with two doses of CoronaVac, a dose of BNT162b2 as a booster substantially enhances immunogenicity reactions and has a relatively acceptable risk for SAEs relative to other vaccines. For primary vaccination, schedules including mRNA vaccines induce a greater immune response. However, the comparatively higher risk for local and systemic adverse events introduced by mRNA vaccines should be noted. REGISTRATION: PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42021278149.

Effectiveness and Cost-Effectiveness of Inactivated Vaccine to Address COVID-19 Pandemic in China: Evidence From Randomized Control Trials and Real-World Studies.

Objective: This study aimed to determine the efficacy, effectiveness, and cost-effectiveness of inactivated COVID-19 vaccines (CoronaVac and BBIBP-CorV) in China using existing international clinical trials and real-world evidence. Methods: Through a search of PubMed, Embase, Web of Science, and CNKI, studies investigating the effectiveness of inactivated COVID-19 vaccines were identified, and a meta-analysis was undertaken to synthesize the vaccine efficacy and effectiveness data. Moreover, a decision-analytic model was developed to estimate the cost-effectiveness of inactivated vaccines for combating the COVID-19 pandemic in the Chinese context from a societal perspective. Results of the meta-analysis, along with cost data from official websites and works of literature were used to populate the model. Sensitivity analysis was performed to test the robustness of the model results. Results: A total of 24 studies were included in the meta-analysis. In comparison to no immunization, the effectiveness of inactivated vaccine against COVID-19 infection, hospitalization, ICU admission and death were 65.18% (95% CI 62.62, 67.75), 79.10% (95% CI 71.69, 86.51), 90.46% (95% CI 89.42, 91.50), and 86.69% (95% CI 85.68, 87.70); and the efficacy against COVID-19 infection and hospitalization were 70.56% (95% CI 57.87, 83.24) and 100% (95% CI 61.72, 100). Inactivated vaccine vaccination prevented more infections, hospitalizations, ICU admissions, and deaths with lower total costs, thus was cost-saving from a societal perspective in China. Base-case analysis results were robust in the one-way sensitivity analysis, and the percentage of ICU admission or death and direct medical cost ranked the top influential factors in our models. In the probabilistic sensitivity analysis, vaccination had a 100% probability of being cost-effective. Conclusion: Inactivated vaccine is effective in preventing COVID-19 infection, hospitalization, ICU admission and avoiding COVID-19 related death, and COVID-19 vaccination program is cost-saving from societal perspective in China.

The effectiveness of influenza vaccine among elderly Chinese: A regression discontinuity design based on Yinzhou regional health information platform.

In China, a free influenza vaccination policy is being implemented among individuals aged 70 years and over in Zhejiang province during the COVID-19 pandemic. The objective was to assess the effectiveness of influenza vaccine in reducing hospitalization and mortality in the elderly. We used data from the Regional Health Information Platform in Yinzhou located in Zhejiang province and applied a regression discontinuity design to estimate the intention-to-treat effect on admission and mortality rates by month of age in the population who was near the age of 70 years threshold. At age 70 years, the influenza vaccination rate increased by 29.1% (95% CI, 28.2% to 29.9%) compared to those under 70 in the study population. When turning age 70 years, the potential effectiveness of receiving influenza vaccine was 8.2% (95% CI, -36.8% to 51.3%) for total hospitalization and the evaluation of vaccine effectiveness was 13.1% (95% CI, -34.2 to 61.8) for the all-cause mortality. An increase in the influenza vaccination rate was associated with a weak decline in most outcomes, but no significance was found for all outcomes. Influenza vaccination had a limited effect on hospital admission and mortality for the free influenza vaccination program that can be related to the low vaccination rate among the Chinese elderly. Supplementation strategies and future studies may be needed to expand immunization coverage and validate this finding, and further provide a reference for other cities to promote the free influenza vaccination policy in China, especially under circumstances of the COVID-19 pandemic.

Ambroxol for the treatment of COVID-19 among hospitalized patients: A multicenter retrospective cohort study.

Ambroxol is a commonly used mucolytic agent principally used to treat respiratory diseases, which may have a role as adjunctive therapy for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, but there is lack of evidence about its effectiveness on coronavirus disease-2019 (COVID-19) patients. To study the association between ambroxol use and clinical outcomes among hospitalized patients of COVID-19 infection. We conducted a multicenter retrospective cohort study involving 3,111 patients with confirmed SARS-CoV-2 infection from three hospitals in Wuhan from 19 December 2019 to 15 April 2020, and the primary outcome was in-hospital mortality. COVID-19 patients were classified into ambroxol and non-ambroxol groups based on the administration of ambroxol during hospitalization. Two analyses including propensity score matching (PSM) to obtain a 1:1 balanced cohort and logistic regression were used to control for confounding factors. The average age of 3,111 patients was 57.55 ± 14.93 years old, 127 of them died during hospitalization, and 924 of them used ambroxol. Treatment with ambroxol did not have a significant effect on in-hospital mortality of COVID-19 patients when compared with non-ambroxol in PSM model after adjusting for confounders (8.0% vs. 3.5%, adjusted OR, 1.03 [95% CI, 0.54-1.97], p = 0.936). Adverse events such as nausea/vomiting, headache, and rash were comparable between the two groups. Our results suggest that the use of ambroxol is not significantly associated with in-hospital mortality in COVID-19 patients, which provides evidence for evaluating the effects of ambroxol on COVID-19 patient outcomes and may be helpful for physicians considering medication alternatives for COVID-19 patients.

Cost-Effectiveness of COVID-19 Sequential Vaccination Strategies in Inactivated Vaccinated Individuals in China.

To effectively prevent and control the COVID-19 pandemic, countries have adopted a booster vaccination strategy. This study aimed to estimate the cost-effectiveness of sequential booster COVID-19 vaccination compared to two-dose inactivated vaccination in China from a societal perspective. A Markov model was developed to estimate the cost-effectiveness of sequential vaccination, including two doses of an inactivated vaccine followed by a booster shot of an inactivated vaccine, adenovirus vectored vaccine, protein subunit vaccine, or mRNA vaccine. The incremental effects of a booster shot with an inactivated vaccine, protein subunit vaccine, adenovirus vectored vaccine, and mRNA vaccine were 0.0075, 0.0110, 0.0208, and 0.0249 QALYs and saved costs of US$163.96, US$261.73, US$583.21, and US$724.49, respectively. Under the Omicron virus pandemic, the sequential vaccination among adults and the elderly (aged 60-69, 70-79, over 80) was consistently cost-saving, and a booster shot of the mRNA vaccine was more cost-saving. The results indicate that the sequential vaccination strategy is cost-effective in addressing the COVID-19 pandemic, and improving vaccination coverage among the elderly is of great importance in avoiding severe cases and deaths.

Analysis on the medication rule of traditional Chinese medicine in the treatment of COVID-19 patients

Objective: To describe patterns of utilization of traditional Chinese medicine (TCM) in the treatment of patients with coronavirus disease 2019 (COVID-19). Methods: Adult patients with COVID-19 who received TCM treatment were divided into a non-serious group (mild and moderate types) and a serious group (severe and critical types) according to their admission conditions. The medical records and prescriptions of these patients were investigated to determine their TCM utilization patterns. Results: In all, 3,872 COVID-19 patients were included. Oral Chinese traditional patent medicine (CPM) was the most commonly used type of TCM, followed by decoction. The proportion of multi-drug combinations was higher than single drug use (55.0% vs. 45.0%). Decoction combined with oral CPM was the most common combination (39.1%, 1,514/3,872). Orally administered, injected, and externally applied CPM were significantly more common in the serious group than in the non-serious, while decoction and non-drug TCM treatments were more common in the non-serious than in the serious group. Multi-drug combinations were used for the majority of patients in both groups, mainly in the form of decoctions combined with oral CPM. Among the serious patients, injected CPM was more often used in patients who died during treatment (35.0%, 36/103). The two most common medication patterns were decoction combined with oral CPM and oral CPM alone in the two finally discharged groups. Oral CPM alone or used in combination with injected CPM were seen most commonly in the death group. Significant differences were established in TCM utilization and medication patterns among patients in three groups who had different prognoses and outcomes. Conclusions: The treatment measures and medication patterns of TCM commonly used in COVID-19 patients with the range of conditions found in this study should be further explored in the future to provide a more complete reference for COVID-19 treatment.

Effectiveness and Cost-Effectiveness of Inactivated Vaccine to Address COVID-19 Pandemic in China: Evidence From Randomized Control Trials and Real-World Studies

Objective This study aimed to determine the efficacy, effectiveness, and cost-effectiveness of inactivated COVID-19 vaccines (CoronaVac and BBIBP-CorV) in China using existing international clinical trials and real-world evidence. Methods Through a search of PubMed, Embase, Web of Science, and CNKI, studies investigating the effectiveness of inactivated COVID-19 vaccines were identified, and a meta-analysis was undertaken to synthesize the vaccine efficacy and effectiveness data. Moreover, a decision-analytic model was developed to estimate the cost-effectiveness of inactivated vaccines for combating the COVID-19 pandemic in the Chinese context from a societal perspective. Results of the meta-analysis, along with cost data from official websites and works of literature were used to populate the model. Sensitivity analysis was performed to test the robustness of the model results. Results A total of 24 studies were included in the meta-analysis. In comparison to no immunization, the effectiveness of inactivated vaccine against COVID-19 infection, hospitalization, ICU admission and death were 65.18% (95% CI 62.62, 67.75), 79.10% (95% CI 71.69, 86.51), 90.46% (95% CI 89.42, 91.50), and 86.69% (95% CI 85.68, 87.70);and the efficacy against COVID-19 infection and hospitalization were 70.56% (95% CI 57.87, 83.24) and 100% (95% CI 61.72, 100). Inactivated vaccine vaccination prevented more infections, hospitalizations, ICU admissions, and deaths with lower total costs, thus was cost-saving from a societal perspective in China. Base-case analysis results were robust in the one-way sensitivity analysis, and the percentage of ICU admission or death and direct medical cost ranked the top influential factors in our models. In the probabilistic sensitivity analysis, vaccination had a 100% probability of being cost-effective. Conclusion Inactivated vaccine is effective in preventing COVID-19 infection, hospitalization, ICU admission and avoiding COVID-19 related death, and COVID-19 vaccination program is cost-saving from societal perspective in China.

Appropriateness of Antibiotic Prescriptions in Chinese Primary Health Care and the Impact of the COVID-19 Pandemic: A Typically Descriptive and Longitudinal Database Study in Yinchuan City.

Background: The appropriateness of antibiotic prescriptions in primary care has not been well evaluated in China in recent years. Furthermore, the impact of coronavirus disease 2019 (COVID-19) on antibiotic prescriptions has not yet been investigated in China. We aimed to assess the appropriateness of antibiotic prescriptions and to evaluate the potential association between the COVID-19 pandemic and antibiotic prescriptions in primary care settings of Yinchuan, a city in China. Methods: This study included 155 primary care institutions and 10,192,713 outpatient visits. Outpatient prescriptions were classified as appropriate, potentially appropriate, inappropriate, or not linked to any diagnosis for antibiotic use following a validated evaluation scheme. Interrupted time-series analyses were performed to assess the effects of the COVID-19 pandemic on antibiotic prescriptions in Chinese primary care facilities. Results: During the study period, 1,287,678 (12.6%, 95% confidence interval [12.6-12.7]) of 10,192,713 outpatient visits in primary care resulted in antibiotic prescriptions. Among 1,287,678 antibiotic prescriptions, 653,335 (50.7% [50.6-50.9]) were inappropriate, 463,081 (36.0% [35.8-36.1]) were potentially appropriate, 171,056 (13.3% [13.1-13.5]) were appropriate, and 206 could not be linked to any diagnosis. Furthermore, patient, physician, and institutional factors were associated with inappropriate antibiotic prescriptions; there was an overall decreasing trend in the proportions of inappropriate antibiotic prescriptions, with the highest level in 2017 (67.1% [66.8-67.5]) and the lowest in 2021 (40.8% [40.3-41.3]). A total of 1,416,120 individual antibiotics were prescribed, of which 1,087,630 (76.8%) were broad-spectrum and 777,672 (54.9%) were classified in the World Health Organization's "Watch" category. In addition, the COVID-19 pandemic was associated with changes of -2.8% (-4.4 to -1.3) in the level and 0.3% (0.2-0.3) in the monthly trend of antibiotic prescription rates, as well as changes of -5.9% (-10.2 to -1.5) in the level and 1.3% (1.0-1.6) in the monthly trend of the proportions of inappropriate antibiotic prescriptions. Conclusion: More than half of the antibiotic prescriptions were inappropriate during the study period in primary care in Yinchuan. The COVID-19 pandemic may be associated with a decrease in the overall and inappropriate use of antibiotics in primary care settings in China.

Comparative effectiveness and safety of 32 pharmacological interventions recommended by guidelines for coronavirus disease 2019: a systematic review and network meta-analysis combining 66 trials.

BACKGROUND: The global pandemic coronavirus disease 2019 (COVID-19) has become a major public health problem and presents an unprecedented challenge. However, no specific drugs were currently proven. This study aimed to evaluate the comparative efficacy and safety of pharmacological interventions in patients with COVID-19. METHODS: Medline, Embase, the Cochrane Library, and clinicaltrials.gov were searched for randomized controlled trials (RCTs) in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/SARS-CoV. Random-effects network meta-analysis within the Bayesian framework was performed, followed by the Grading of Recommendations Assessment, Development, and Evaluation system assessing the quality of evidence. The primary outcome of interest includes mortality, cure, viral negative conversion, and overall adverse events (OAEs). Odds ratio (OR) with 95% confidence interval (CI) was calculated as the measure of effect size. RESULTS: Sixty-six RCTs with 19,095 patients were included, involving standard of care (SOC), eight different antiviral agents, six different antibiotics, high and low dose chloroquine (CQ_HD, CQ_LD), traditional Chinese medicine (TCM), corticosteroids (COR), and other treatments. Compared with SOC, a significant reduction of mortality was observed for TCM (OR = 0.34, 95% CI: 0.20-0.56, moderate quality) and COR (OR = 0.84, 95% CI: 0.75-0.96, low quality) with improved cure rate (OR = 2.16, 95% CI: 1.60-2.91, low quality for TCM; OR = 1.17, 95% CI: 1.05-1.30, low quality for COR). However, an increased risk of mortality was found for CQ_HD vs. SOC (OR = 3.20, 95% CI: 1.18-8.73, low quality). TCM was associated with decreased risk of OAE (OR = 0.52, 95% CI: 0.38-0.70, very low quality) but CQ_HD (OR = 2.51, 95% CI: 1.20-5.24) and interferons (IFN) (OR = 2.69, 95% CI: 1.02-7.08) vs. SOC with very low quality were associated with an increased risk. CONCLUSIONS: COR and TCM may reduce mortality and increase cure rate with no increased risk of OAEs compared with standard care. CQ_HD might increase the risk of mortality. CQ, IFN, and other antiviral agents could increase the risk of OAEs. The current evidence is generally uncertain with low-quality and further high-quality trials are needed.

An analytical study of drug utilization, disease progression, and adverse events among 165 COVID-19 patients.

BACKGROUND: The coronavirus disease 2019 (COVID-19) epidemic has lasted for nearly 4 months by this study was conducted. We aimed to describe drug utilization, disease progression, and adverse drug events of COVID-19. METHODS: A retrospective, single-center case series study enrolled 165 consecutive hospitalized COVID-19 patients who were followed up until March 25, 2020, from a designated hospital in Wuhan. Patients were grouped by a baseline degree of severity: non-severe and severe. An analytical study of drug utilization, disease progression, and adverse events (AEs) of COVID-19 was conducted. RESULTS: Of the 165 COVID-19 cases, antivirals, antibacterials, glucocorticoids, and traditional Chinese medicine (TCM) were administered to 92.7%, 98.8%, 68.5%, and 55.2% of patients, respectively. The total kinds of drugs administered to the severe subgroup [26, interquartile range (IQR) 18-39] were 11 more than the non-severe subgroup (15, IQR 10-24), regardless of comorbidities. The 2 most common combinations of medications in the 165 cases were 'antiviral therapy + glucocorticoids + TCM' (81, 49.1%) and 'antiviral therapy + glucocorticoids' (23, 13.9%). Compared with non-severe cases, severe cases received more glucocorticoids (88.5% vs. 66.2%, P=0.02), but less TCM (50.0% vs. 63.3%, P=0.20), and suffered a higher percentage of death (34.6% vs. 7.2%, P=0.001). At the end of the follow-up, 130 (78.8%) patients had been discharged, and 24 (14.5%) died. There were 13 patients (7.9%) who had elevated liver enzymes, and 49 patients (29.7%) presented with worsening kidney function during the follow-up. CONCLUSIONS: Of the 165 COVID-19 patients, the fatality rate remained high (14.5%). Drug utilization for COVID-19 was diverse and generally complied with the existing guidelines. Combination regimens containing antiviral drugs might be beneficial to assist COVID-19 recovery. Additionally, liver and kidney AEs should not be ignored.

A scientificity and feasibility evaluation of COVID-19 clinical studies registered in China.

BACKGROUND: An outbreak of novel coronavirus infection in Wuhan, China, in early 2020 has now developed into a worldwide pandemic. Researchers in China and around the world have conducted many clinical studies on the scientific response to infectious diseases. Here, we review and summarize the registration protocols for clinical research of the novel coronavirus disease (COVID-19). METHODS: We searched all the registered studies in all platforms under the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) before March 11, 2020, screened the registration scheme for novel coronavirus, extracted the basic research information, research quality, feasibility information, and described the scientificity and feasibility of interventional research. RESULTS: From January 23, 2020 to March 11, 2020, 379 clinical studies were registered, 260 were therapeutic studies among them, and 96.8% studies were conducted in China by Chinese researchers. Some studies were registered 2 weeks just after the virus was identified, and up to 22 studies registered for one day. The number of interventional studies was greater than observational studies (263 vs. 116). Among the interventional studies, nearly 50% studies were funded, 87.7% were randomized, and 79.4% of the primary outcome indicators were objective. However, the sample size of the studies ranged from 60 to 200, with the total sample size accounting for 40% of the confirmed infected population. More than 60% studies might face the problem of insufficient sample size. CONCLUSIONS: COVID-19 clinical study registration has been considerable, rapid, and high quality in study design. However, the feasibility of these studies may still be problematic, especially in such as insufficient sample size, poor coordination among multidisciplinary teams, and weak quality control in the research process.

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late phase in critically ill patients with SARS-CoV-2. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. METHODS: The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2-infected Vero cells. Physiologically based pharmacokinetic (PBPK) models were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen while considering the drug's safety profile. RESULTS: Hydroxychloroquine (EC50 = 0.72 µM) was found to be more potent than chloroquine (EC50 = 5.47 µM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached 3 times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. CONCLUSIONS: Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.