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      Physiologically‐Based Pharmacokinetic Modeling of Remdesivir and Its Metabolites to Support Dose Selection for the Treatment of Pediatric Patients With COVID‐19

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          Abstract

          Severe coronavirus disease 2019 (COVID‐19) disease, including multisystem inflammatory syndrome, has been reported in children. This report summarizes development of a remdesivir physiologically‐based pharmacokinetic (PBPK) model that accurately describes observed adult remdesivir and metabolites exposure and predicts pediatric remdesivir and metabolites exposure. The adult PBPK model was applied to predict pediatric remdesivir and metabolites steady‐state exposures using the Pediatric Population Model in SimCYP and incorporated the relevant physiologic and mechanistic information. Model development was based on adult phase I exposure data in healthy volunteers who were administered a 200‐mg loading dose of remdesivir intravenous (IV) over 0.5 hours on Day 1, then 100‐mg daily maintenance doses of IV over 0.5 hours starting on Day 2 and continuing through Days 5 or 10. Simulations indicated that use of the adult therapeutic remdesivir dosage regimen (200‐mg loading dose on Day 1 then 100‐mg daily maintenance dose starting on Day 2) in pediatric patients ≥ 40 kg and a weight‐based remdesivir dosage regimen (5‐mg/kg loading dose on Day 1 then 2.5‐mg/kg daily maintenance dose starting on Day 2) in pediatric patients weighing 2.5 to < 40 kg is predicted to maintain therapeutic exposures of remdesivir and its metabolites. The comprehensive PBPK model described in this report supported remdesivir dosing in planned pediatric clinical studies and dosing in the emergency use authorization and pediatric compassionate use programs that were initiated to support remdesivir as a treatment option during the pandemic.

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          WHO Declares COVID-19 a Pandemic

          The World Health Organization (WHO) on March 11, 2020, has declared the novel coronavirus (COVID-19) outbreak a global pandemic (1). At a news briefing, WHO Director-General, Dr. Tedros Adhanom Ghebreyesus, noted that over the past 2 weeks, the number of cases outside China increased 13-fold and the number of countries with cases increased threefold. Further increases are expected. He said that the WHO is “deeply concerned both by the alarming levels of spread and severity and by the alarming levels of inaction,” and he called on countries to take action now to contain the virus. “We should double down,” he said. “We should be more aggressive.” Among the WHO’s current recommendations, people with mild respiratory symptoms should be encouraged to isolate themselves, and social distancing is emphasized and these recommendations apply even to countries with no reported cases (2). Separately, in JAMA, researchers report that SARS-CoV-2, the virus that causes COVID-19, was most often detected in respiratory samples from patients in China. However, live virus was also found in feces. They conclude: “Transmission of the virus by respiratory and extrarespiratory routes may help explain the rapid spread of disease.”(3). COVID-19 is a novel disease with an incompletely described clinical course, especially for children. In a recente report W. Liu et al described that the virus causing Covid-19 was detected early in the epidemic in 6 (1.6%) out of 366 children (≤16 years of age) hospitalized because of respiratory infections at Tongji Hospital, around Wuhan. All these six children had previously been completely healthy and their clinical characteristics at admission included high fever (>39°C) cough and vomiting (only in four). Four of the six patients had pneumonia, and only one required intensive care. All patients were treated with antiviral agents, antibiotic agents, and supportive therapies, and recovered after a median 7.5 days of hospitalization. (4). Risk factors for severe illness remain uncertain (although older age and comorbidity have emerged as likely important factors), the safety of supportive care strategies such as oxygen by high-flow nasal cannula and noninvasive ventilation are unclear, and the risk of mortality, even among critically ill patients, is uncertain. There are no proven effective specific treatment strategies, and the risk-benefit ratio for commonly used treatments such as corticosteroids is unclear (3,5). Septic shock and specific organ dysfunction such as acute kidney injury appear to occur in a significant proportion of patients with COVID-19–related critical illness and are associated with increasing mortality, with management recommendations following available evidence-based guidelines (3). Novel COVID-19 “can often present as a common cold-like illness,” wrote Roman Wöelfel et al. (6). They report data from a study concerning nine young- to middle-aged adults in Germany who developed COVID-19 after close contact with a known case. All had generally mild clinical courses; seven had upper respiratory tract disease, and two had limited involvement of the lower respiratory tract. Pharyngeal virus shedding was high during the first week of symptoms, peaking on day 4. Additionally, sputum viral shedding persisted after symptom resolution. The German researchers say the current case definition for COVID-19, which emphasizes lower respiratory tract disease, may need to be adjusted(6). But they considered only young and “normal” subjecta whereas the story is different in frail comorbid older patients, in whom COVID 19 may precipitate an insterstitial pneumonia, with severe respiratory failure and death (3). High level of attention should be paid to comorbidities in the treatment of COVID-19. In the literature, COVID-19 is characterised by the symptoms of viral pneumonia such as fever, fatigue, dry cough, and lymphopenia. Many of the older patients who become severely ill have evidence of underlying illness such as cardiovascular disease, liver disease, kidney disease, or malignant tumours. These patients often die of their original comorbidities. They die “with COVID”, but were extremely frail and we therefore need to accurately evaluate all original comorbidities. In addition to the risk of group transmission of an infectious disease, we should pay full attention to the treatment of the original comorbidities of the individual while treating pneumonia, especially in older patients with serious comorbid conditions and polipharmacy. Not only capable of causing pneumonia, COVID-19 may also cause damage to other organs such as the heart, the liver, and the kidneys, as well as to organ systems such as the blood and the immune system. Patients die of multiple organ failure, shock, acute respiratory distress syndrome, heart failure, arrhythmias, and renal failure (5,6). What we know about COVID 19? In December 2019, a cluster of severe pneumonia cases of unknown cause was reported in Wuhan, Hubei province, China. The initial cluster was epidemiologically linked to a seafood wholesale market in Wuhan, although many of the initial 41 cases were later reported to have no known exposure to the market (7). A novel strain of coronavirus belonging to the same family of viruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as the 4 human coronaviruses associated with the common cold, was subsequently isolated from lower respiratory tract samples of 4 cases on 7 January 2020. On 30 January 2020, the WHO declared that the SARS-CoV-2 outbreak constituted a Public Health Emergency of International Concern, and more than 80, 000 confirmed cases had been reported worldwide as of 28 February 2020 (8). On 31 January 2020, the U.S. Centers for Disease Control and Prevention announced that all citizens returning from Hubei province, China, would be subject to mandatory quarantine for up to 14 days. But from China COVID 19 arrived to many other countries. Rothe C et al reported a case of a 33-year-old otherwise healthy German businessman :she became ill with a sore throat, chills, and myalgias on January 24, 2020 (9). The following day, a fever of 39.1°C developed, along with a productive cough. By the evening of the next day, he started feeling better and went back to work on January 27. Before the onset of symptoms, he had attended meetings with a Chinese business partner at his company near Munich on January 20 and 21. The business partner, a Shanghai resident, had visited Germany between January 19 and 22. During her stay, she had been well with no signs or symptoms of infection but had become ill on her flight back to China, where she tested positive for 2019-nCoV on January 26. This case of 2019-nCoV infection was diagnosed in Germany and transmitted outside Asia. However, it is notable that the infection appears to have been transmitted during the incubation period of the index patient, in whom the illness was brief and nonspecific. The fact that asymptomatic persons are potential sources of 2019-nCoV infection may warrant a reassessment of transmission dynamics of the current outbreak (9). Our current understanding of the incubation period for COVID-19 is limited. An early analysis based on 88 confirmed cases in Chinese provinces outside Wuhan, using data on known travel to and from Wuhan to estimate the exposure interval, indicated a mean incubation period of 6.4 days (95% CI, 5.6 to 7.7 days), with a range of 2.1 to 11.1 days. Another analysis based on 158 confirmed cases outside Wuhan estimated a median incubation period of 5.0 days (CI, 4.4 to 5.6 days), with a range of 2 to 14 days. These estimates are generally consistent with estimates from 10 confirmed cases in China (mean incubation period, 5.2 days [CI, 4.1 to 7.0 days] and from clinical reports of a familial cluster of COVID-19 in which symptom onset occurred 3 to 6 days after assumed exposure in Wuhan (10-12). The incubation period can inform several important public health activities for infectious diseases, including active monitoring, surveillance, control, and modeling. Active monitoring requires potentially exposed persons to contact local health authorities to report their health status every day. Understanding the length of active monitoring needed to limit the risk for missing infections is necessary for health departments to effectively use resources. A recent paper provides additional evidence for a median incubation period for COVID-19 of approximately 5 days (13). Lauer et al suggest that 101 out of every 10 000 cases will develop symptoms after 14 days of active monitoring or quarantinen (13). Whether this rate is acceptable depends on the expected risk for infection in the population being monitored and considered judgment about the cost of missing cases. Combining these judgments with the estimates presented here can help public health officials to set rational and evidence-based COVID-19 control policies. Note that the proportion of mild cases detected has increased as surveillance and monitoring systems have been strengthened. The incubation period for these severe cases may differ from that of less severe or subclinical infections and is not typically an applicable measure for those with asymptomatic infections In conclusion, in a very short period health care systems and society have been severely challenged by yet another emerging virus. Preventing transmission and slowing the rate of new infections are the primary goals; however, the concern of COVID-19 causing critical illness and death is at the core of public anxiety. The critical care community has enormous experience in treating severe acute respiratory infections every year, often from uncertain causes. The care of severely ill patients, in particular older persons with COVID-19 must be grounded in this evidence base and, in parallel, ensure that learning from each patient could be of great importance to care all population,
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            Multisystem Inflammatory Syndrome in U.S. Children and Adolescents

            Abstract Background Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. Methods We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. Results We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). Conclusions Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)
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              Coronavirus Disease 2019 in Children — United States, February 12–April 2, 2020

              On April 6, 2020, this report was posted online as an MMWR Early Release. As of April 2, 2020, the coronavirus disease 2019 (COVID-19) pandemic has resulted in >890,000 cases and >45,000 deaths worldwide, including 239,279 cases and 5,443 deaths in the United States ( 1 , 2 ). In the United States, 22% of the population is made up of infants, children, and adolescents aged * Includes infants, children, and adolescents. † Excludes 23 cases in children aged <18 years with missing report date. § Date of report available starting February 24, 2020; reported cases include any with onset on or after February 12, 2020. The figure is a combination epidemiological curve and line graph showing 2,549 cases of COVID-19 in children aged <18 years in the United States, by date reported to CDC during February 24–April 2, 2020. Among all 2,572 COVID-19 cases in children aged <18 years, the median age was 11 years (range 0–17 years). Nearly one third of reported pediatric cases (813; 32%) occurred in children aged 15–17 years, followed by those in children aged 10–14 years (682; 27%). Among younger children, 398 (15%) occurred in children aged <1 year, 291 (11%) in children aged 1–4 years, and 388 (15%) in children aged 5–9 years. Among 2,490 pediatric COVID-19 cases for which sex was known, 1,408 (57%) occurred in males; among cases in adults aged ≥18 years for which sex was known, 53% (75,450 of 143,414) were in males. Among 184 (7.2%) cases in children aged <18 years with known exposure information, 16 (9%) were associated with travel and 168 (91%) had exposure to a COVID-19 patient in the household or community. Data on signs and symptoms of COVID-19 were available for 291 of 2,572 (11%) pediatric cases and 10,944 of 113,985 (9.6%) cases among adults aged 18–64 years (Table). Whereas fever (subjective or documented), cough, and shortness of breath were commonly reported among adult patients aged 18–64 years (93% reported at least one of these), these signs and symptoms were less frequently reported among pediatric patients (73%). Among those with known information on each symptom, 56% of pediatric patients reported fever, 54% reported cough, and 13% reported shortness of breath, compared with 71%, 80%, and 43%, respectively, reporting these signs and symptoms among patients aged 18–64 years. Myalgia, sore throat, headache, and diarrhea were also less commonly reported by pediatric patients. Fifty-three (68%) of the 78 pediatric cases reported not to have fever, cough, or shortness of breath had no symptoms reported, but could not be classified as asymptomatic because of incomplete symptom information. One (1.3%) additional pediatric patient with a positive test result for SARS-CoV-2 was reported to be asymptomatic. TABLE Signs and symptoms among 291 pediatric (age <18 years) and 10,944 adult (age 18–64 years) patients* with laboratory-confirmed COVID-19 — United States, February 12–April 2, 2020 Sign/Symptom No. (%) with sign/symptom Pediatric Adult Fever, cough, or shortness of breath† 213 (73) 10,167 (93) Fever§ 163 (56) 7,794 (71) Cough 158 (54) 8,775 (80) Shortness of breath 39 (13) 4,674 (43) Myalgia 66 (23) 6,713 (61) Runny nose¶ 21 (7.2) 757 (6.9) Sore throat 71 (24) 3,795 (35) Headache 81 (28) 6,335 (58) Nausea/Vomiting 31 (11) 1,746 (16) Abdominal pain¶ 17 (5.8) 1,329 (12) Diarrhea 37 (13) 3,353 (31) *Cases were included in the denominator if they had a known symptom status for fever, cough, shortness of breath, nausea/vomiting, and diarrhea. Total number of patients by age group: <18 years (N = 2,572), 18–64 years (N = 113,985). † Includes all cases with one or more of these symptoms. § Patients were included if they had information for either measured or subjective fever variables and were considered to have a fever if “yes” was indicated for either variable. ¶ Runny nose and abdominal pain were less frequently completed than other symptoms; therefore, percentages with these symptoms are likely underestimates. Information on hospitalization status was available for 745 (29%) cases in children aged <18 years and 35,061 (31%) cases in adults aged 18–64 years. Among children with COVID-19, 147 (estimated range = 5.7%–20%) were reported to be hospitalized, with 15 (0.58%–2.0%) admitted to an ICU (Figure 2). Among adults aged 18–64 years, the percentages of patients who were hospitalized (10%–33%), including those admitted to an ICU (1.4%–4.5%), were higher. Children aged <1 year accounted for the highest percentage (15%–62%) of hospitalization among pediatric patients with COVID-19. Among 95 children aged <1 year with known hospitalization status, 59 (62%) were hospitalized, including five who were admitted to an ICU. The percentage of patients hospitalized among those aged 1–17 years was lower (estimated range = 4.1%–14%), with little variation among age groups (Figure 2). FIGURE 2 COVID-19 cases among children* aged <18 years, among those with known hospitalization status (N = 745),† by age group and hospitalization status — United States, February 12–April 2, 2020 Abbreviation: ICU = intensive care unit. * Includes infants, children, and adolescents. † Number of children missing hospitalization status by age group: <1 year (303 of 398; 76%); 1–4 years (189 of 291; 65%); 5–9 years (275 of 388; 71%); 10–14 years (466 of 682; 68%); 15–17 years (594 of 813; 73%). The figure is a bar chart showing 745 U.S. COVID-19 cases among children aged <18 years with known hospitalization status, by age group and hospitalization status during February 12–April 2, 2020. Among 345 pediatric cases with information on underlying conditions, 80 (23%) had at least one underlying condition. The most common underlying conditions were chronic lung disease (including asthma) (40), cardiovascular disease (25), and immunosuppression (10). Among the 295 pediatric cases for which information on both hospitalization status and underlying medical conditions was available, 28 of 37 (77%) hospitalized patients, including all six patients admitted to an ICU, had one or more underlying medical condition; among 258 patients who were not hospitalized, 30 (12%) patients had underlying conditions. Three deaths were reported among the pediatric cases included in this analysis; however, review of these cases is ongoing to confirm COVID-19 as the likely cause of death. Discussion Among 149,082 U.S. cases of COVID-19 reported as of April 2, 2020, for which age was known, 2,572 (1.7%) occurred in patients aged <18 years. In comparison, persons aged <18 years account for 22% of the U.S. population ( 3 ). Although infants <1 year accounted for 15% of pediatric COVID-19 cases, they remain underrepresented among COVID-19 cases in patients of all ages (393 of 149,082; 0.27%) compared with the percentage of the U.S. population aged <1 year (1.2%) ( 3 ). Relatively few pediatric COVID-19 cases were hospitalized (5.7%–20%; including 0.58%–2.0% admitted to an ICU), consistent with previous reports that COVID-19 illness often might have a mild course among younger patients ( 4 , 5 ). Hospitalization was most common among pediatric patients aged <1 year and those with underlying conditions. In addition, 73% of children for whom symptom information was known reported the characteristic COVID-19 signs and symptoms of fever, cough, or shortness of breath. These findings are largely consistent with a report on pediatric COVID-19 patients aged <16 years in China, which found that only 41.5% of pediatric patients had fever, 48.5% had cough, and 1.8% were admitted to an ICU ( 4 ). A second report suggested that although pediatric COVID-19 patients infrequently have severe outcomes, the infection might be more severe among infants ( 5 ). In the current analysis, 59 of 147 pediatric hospitalizations, including five of 15 pediatric ICU admissions, were among children aged <1 year; however, most reported U.S. cases in infants had unknown hospitalization status. In this preliminary analysis of U.S. pediatric COVID-19 cases, a majority (57%) of patients were males. Several studies have reported a majority of COVID-19 cases among males ( 4 , 9 ), and an analysis of 44,000 COVID-19 cases in patients of all ages in China reported a higher case-fatality rate among men than among women ( 10 ). However, the same report, as well as a separate analysis of 2,143 pediatric COVID-19 cases from China, detected no substantial difference in the number of cases among males and females ( 5 , 10 ). Reasons for any potential difference in COVID-19 incidence or severity between males and females are unknown. In the present analysis, the predominance of males in all pediatric age groups, including patients aged <1 year, suggests that biologic factors might play a role in any differences in COVID-19 susceptibility by sex. The findings in this report are subject to at least four limitations. First, because of the high workload associated with COVID-19 response activities on local, state, and territorial public health personnel, a majority of pediatric cases were missing data on disease symptoms, severity, or underlying conditions. Data for many variables are unlikely to be missing at random, and as such, these results must be interpreted with caution. Because of the high percentage of missing data, statistical comparisons could not be conducted. Second, because many cases occurred only days before publication of this report, the outcome for many patients is unknown, and this analysis might underestimate severity of disease or symptoms that manifested later in the course of illness. Third, COVID-19 testing practices differ across jurisdictions and might also differ across age groups. In many areas, prioritization of testing for severely ill patients likely occurs, which would result in overestimation of the percentage of patients with COVID-19 infection who are hospitalized (including those treated in an ICU) among all age groups. Finally, this analysis compares clinical characteristics of pediatric cases (persons aged <18 years) with those of cases among adults aged 18–64 years. Severe COVID-19 disease appears to be more common among adults at the high end of this age range ( 6 ), and therefore cases in young adults might be more similar to those among children than suggested by the current analysis. As the number of COVID-19 cases continues to increase in many parts of the United States, it will be important to adapt COVID-19 surveillance strategies to maintain collection of critical case information without overburdening jurisdiction health departments. National surveillance will increasingly be complemented by focused surveillance systems collecting comprehensive case information on a subset of cases across various health care settings. These systems will provide detailed information on the evolving COVID-19 incidence and risk factors for infection and severe disease. More systematic and detailed collection of underlying condition data among pediatric patients would be helpful to understand which children might be at highest risk for severe COVID-19 illness. This preliminary examination of characteristics of COVID-19 disease among children in the United States suggests that children do not always have fever or cough as reported signs and symptoms. Although most cases reported among children to date have not been severe, clinicians should maintain a high index of suspicion for COVID-19 infection in children and monitor for progression of illness, particularly among infants and children with underlying conditions. However, these findings must be interpreted with caution because of the high percentage of cases missing data on important characteristics. Because persons with asymptomatic and mild disease, including children, are likely playing a role in transmission and spread of COVID-19 in the community, social distancing and everyday preventive behaviors are recommended for persons of all ages to slow the spread of the virus, protect the health care system from being overloaded, and protect older adults and persons of any age with serious underlying medical conditions. Recommendations for reducing the spread of COVID-19 by staying at home and practicing strategies such as respiratory hygiene, wearing cloth face coverings when around others, and others are available on CDC’s coronavirus website at https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Summary What is already known about this topic? Data from China suggest that pediatric coronavirus disease 2019 (COVID-19) cases might be less severe than cases in adults and that children (persons aged <18 years) might experience different symptoms than adults. What is added by this report? In this preliminary description of pediatric U.S. COVID-19 cases, relatively few children with COVID-19 are hospitalized, and fewer children than adults experience fever, cough, or shortness of breath. Severe outcomes have been reported in children, including three deaths. What are the implications for public health practice? Pediatric COVID-19 patients might not have fever or cough. Social distancing and everyday preventive behaviors remain important for all age groups because patients with less serious illness and those without symptoms likely play an important role in disease transmission.
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                Author and article information

                Contributors
                justin.lutz@gilead.com
                Journal
                Clin Pharmacol Ther
                Clin Pharmacol Ther
                10.1002/(ISSN)1532-6535
                CPT
                Clinical Pharmacology and Therapeutics
                John Wiley and Sons Inc. (Hoboken )
                0009-9236
                1532-6535
                10 March 2021
                April 2021
                : 109
                : 4 , Therapeutic Innovations in Infectious Diseases ( doiID: 10.1002/cpt.v109.4 )
                : 1116-1124
                Affiliations
                [ 1 ] Department of Clinical Pharmacology Gilead Sciences Inc. Foster City California USA
                [ 2 ] Department of Clinical Research Gilead Sciences Inc. Foster City California USA
                Author notes
                [*] [* ] Correspondence: Justin D. Lutz ( justin.lutz@ 123456gilead.com )

                Article
                CPT2176
                10.1002/cpt.2176
                8014571
                33501997
                701e4231-1b15-44bb-837b-c1be6acb3e39
                © 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                History
                : 26 October 2020
                : 01 January 2021
                Page count
                Figures: 4, Tables: 1, Pages: 9, Words: 6027
                Funding
                Funded by: Gilead Sciences, Inc
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                April 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.1 mode:remove_FC converted:01.04.2021

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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