20220114-COVID-19治療

Treatment of
COVID-19
新冠肺炎治療
曾鈺婷醫師
高雄榮民總醫院內科部感染科
2022年01月14日
1

outline
COVID-19簡介
藥物治療
氧氣治療
2

outline
COVID-19簡介
藥物治療
氧氣治療
3

4
Clin Microbiol Rev. 2015 Apr;28(2):465-522.Wit et al.
Nat Rev Microbiol. 2016 Aug;14(8):523-34.
SARS-CoV-2
單股RNA病毒
Spike
envelope
nucleocapsid membrane

COVID-19 疾病介紹
• 潛伏期：1-14天 (平均5-6天)
• 可傳染期：發病前2天-發病後10天 (少數病人可能更久)
• 傳播途徑：
• 近距離飛沫傳染、直接或間接之接觸傳染
• 防護方式
• 一般醫療行為：外科口罩、隔離衣、手套
• 會誘發氣霧的醫療行為 (Aerosol-generating procedures, AGP)：
N95口罩、面罩或護目鏡、隔離衣、手套
5

6
Cevik et al. Clin Infect Dis. 2020. DOI: 10.1093/cid/ciaa1442
SARS-CoV-2 病毒量隨時間之變化圖

COVID-19臨床表現
• 約30%感染者無症狀
• 有症狀者，與一般病毒性上呼吸道感染很難區分
• 有症狀者
• 常見：發燒、乾咳、倦怠、鼻塞/流鼻水
• 偶見：肌肉痠痛、頭痛、喉嚨痛、腹瀉
• 少數：嗅味覺異常
• 約三分之一的有症狀感染者會有氣促的症狀
7
新型冠狀病毒（SARS-CoV-2）感染臨床處置暫行指引第十五版

Endocrine
 Hyperglycemia
 Diabetic ketoacidosis
Extrapulmonary Manifestations
Gupta. Nat Med. 2020;26:1017. Slide credit: clinicaloptions.com
Neurologic
 Headaches
 Dizziness
 Encephalopathy
 Guillain-Barré
Renal
 Acute kidney injury
 Proteinuria
 Hematuria
Hepatic
 Elevated ALT/AST
 Elevated bilirubin
Cardiac
 Takotsubo cardiomyopathy
 Myocardial injury/myocarditis
 Cardiac arrhythmias
 Ageusia
 Myalgia
 Anosmia
 Stroke
 Cardiogenic shock
 Myocardial ischemia
 Acute cor pulmonale
Dermatologic
 Petechaie
 Livedo reticularis
 Erythematous rash
 Urticaria
 Vesicles
 Pernio-like lesions
Thromboembolism
 Deep vein thrombosis
 Pulmonary embolism
 Catheter-related thrombosis
Gastrointestinal
 Diarrhea
 Nausea/vomiting
 Abdominal pain
 Anorexia
8

COVID-19 嚴重程度
• 無症狀感染者：30% (美國CDC估計)
• 有症狀感染者中有80%為輕症
• 重症：14%  需要氧氣或住院治療
• 需要加護病房照顧：5%
• 整體死亡率1.8% (美國經驗)
• ICU 病患 90 天死亡率： 30-50% (歐洲經驗)
9
US CDC website. https://www.cdc.gov/coronavirus/2019-ncov/hcp/planning-scenarios.html Assessed June 3, 2021

COVID-19臨床表現分類
(參考 WHO, NIH 與 IDSA)
輕度無併發症之輕症沒有併發症
中度肺炎無用氧時SpO2 >94%
重度嚴重肺炎
呼吸>30,
PaO2/FiO2<300
無用氧時SpO2 ≤94%
肺浸潤 (infiltration)>50%
極重度
急性呼吸窘迫症候群（ARDS）
敗血症
敗血性休克
孩童多系統炎症徵候群(Multisystem
inflammatory syndrome in children, MIS-C) 10

COVID-19臨床表現(我國前1184 例確診個案
之初始症狀)
咳嗽發燒流鼻水/鼻塞嗅覺異常味覺異常
31.8% 26.9% 17.0% 11.8% 8.0%
為無併發症之輕
症或無症狀感染
83%
肺炎 11%
嚴重肺炎與ARDS 6%
死亡率約1%
11

併發症發生時間
大部分在疾病的
第7-10天惡化
12

COVID-19 重症之危險因子
• 年紀
• 慢性疾病
• 心血管疾病、腦血管疾病、慢性肺病
• 糖尿病、代謝症候群、高血壓
• 癌症患者、免疫不全者
• 吸菸史
• 孕婦
13

不良預後因子
Test Valve Normal value*
WBC >10,000 4,100-10,500/ul
Lymphocyte <1,000 (20.7- 49.2%)
PLT <150 160-370 K/uL
D-dimer >1,000 <500 ng/ml
Albumin <3 3.5-5.7 g/dL
CK >185 M: 27-168 U/L
F: 24-120 U/L
Crea >1.5 M: 0.7-1.3 mg/dL
F: 0.6-1.2 mg/ dL
ALT(GPT) >40 0-40 U/L
LDH >245 95-213 U/L
Test Valve Normal value*
Hs-TnT >20 M: <= 19.8 ; F: <= 11.6
ng/L=pg/mL
CRP >12.5 <1.0 mg/dL
Ferritin >300 M: 23.9-336.2 ng/mL
F: 11.0-306.8 ng/mL
Procalcitonin >0.5 <0.07 ng/mL
IL-6 >10 (pg /mL) 本院無參考值
Zhou F Lancet. 2020 Mar 28;395(10229):1054-1062
Huang C Lancet. 2020 Feb 15;395(10223):497-506
Chen N Lancet. 2020 Feb 15;395(10223):507-513
Wu C JAMA Intern Med. 2020 Jul 1;180(7):934-943
RuanQ. Intensive Care Med. 2020 May;46(5):846-848
* 為高雄榮總檢驗部參考值
14

我國的COVID-19
截至 2021年 12月 25日止，公布之 16,873例確診個
案中
• 約 30%為 60歲以上長者
• 15%為嚴重肺炎或 ARDS之重症個案
•重症個案約七成為 60歲以上長者
15

新冠病毒感染期與治療簡要
第一期感染早期
(輕度) D1-D5
肺部侵犯早期
(中度)
肺部侵犯晚期
(重度)
病毒反應期
宿主免疫發炎反應期
疾
病
嚴
重
度
時間病程
臨床症狀
臨床病徵
治療方法
輕微全身性症狀、發燒、乾咳、喉
嚨痛、腹瀉、味嗅覺異常或消失
淋巴球低下
成人呼吸窘迫症候群
全身性發炎反應/休克
心肺衰竭
發炎標記上升
CRP、PCT、LDH、D-dimer、IL-6,TNF-α
第二期肺部侵犯
D5-D10
第三期激素風暴期
(極重度) D7-D10
喘 RR>30/min
影像異常、肝功能上升、低或正常
的procalcitonin
NIH COVID-19 Treatment Guidelines. Clinical management summary. Last updated December 16, 2021.
Siddiqi. J Heart Lung Transplant. 2020;39:405.
缺氧
避免免疫抑制; 抗病毒藥物抑制過度發炎; 抗凝血
16

COVID-19 治療原則概要
• Mild 輕度(活動自如): 支持性療法、(單株抗體、remdesivir)
• Moderate 中度(SpO2≥95%): 支持性療法、(單株抗體、
remdesivir)
• Severe 重度(SpO2≤94%): 氧氣、remdesivir、dexamethasone、
• Critical 危急(Endo, ICU, ARDS):重症照護、dexamethasone
• 重點1：辨識從中度轉為重度的病人 給氧、給藥
• 重點2：辨識從重度轉為危急的病人 插管、重症照護
17

outline
COVID-19簡介
藥物治療
氧氣治療
18

COVID-19 藥物治療
Corticosteroids 類固醇
19

Randomized Evaluation of COVID-19 Therapy
(RECOVERY) Trial
• 臨床診斷或實驗室確診COVID-19住院病人
• 隨機分成 usual care +
• no additional treatment
• Lopinavir/ritonavir
• Dexamethasone (6mg QD *~10 days)
• Hydroxychloroquine
• Azithromycin
• 同時再分成有無使用convalescent plasma(恢復期血清)
• 若疾病再惡化，再分成有無使用 tocilizumab
20

RECOVERY Trial
• 臨床診斷或實驗室確診COVID-19住院病人
• Patients randomized to usual care plus: no additional
tx, lopinavir/ritonavir, dexamethasone,
hydroxychloroquine, or azithromycin
RECOVERY Collaborative Group. NEJM. 2021;384:693.
21

RECOVERY Trial- Baseline Characteristics
Characteristic
Treatment Allocation Respiratory Support at Randomization
Dexamethason
e + Usual Care
(n = 2104)
Usual Care
Only
(n = 4321)
No Oxygen
(n = 1535)
Oxygen Only
(n = 3883)
Invasive
Mechanical
Ventilation
(n = 1007)
Mean age, yr (SD)
 <70
 70 to 79
 ≥80
66.9 (15.4)
1141 (54)
469 (22)
494 (23)
65.8 (15.8)
2504 (58)
859 (20)
958 (22)
69.4 (17.5)
659 (43)
338 (22)
538 (35)
66.7 (15.3)
2148 (55)
837 (22)
898 (23)
59.1 (11.4)
838 (83)
153 (15)
16 (2)
Male sex, n (%) 1338 (64) 2749 (64) 891 (58) 2462 (63) 734 (73)
Median time from symptom onset
to randomization,* days(IQR)
8 (5-13) 9 (5-13) 6 (3-10) 9 (5-12) 13 (8-18)
SARS-CoV-2 PCR result, n (%)
 Positive
 Negative
 Not yet known
1850 (88)
247 (12)
7 (<1)
3848 (89)
453 (10)
20 (<1)
1333 (87)
193 (13)
9 (1)
3416 (88)
452 (12)
15 (<1)
949 (94)
55 (5)
3 (<1)
22

RECOVERY Trial- Comorbidities
Previous Disease, n (%)
Treatment Allocation Respiratory Support at Randomization
Dexamethasone
+ Usual Care
(n = 2104)
Usual Care
Only
(n = 4321)
No Oxygen
(n = 1535)
Oxygen Only
(n = 3883)
Invasive
Mechanical
Ventilation
(n = 1007)
Any 1174 (56) 2417 (56) 911 (59) 2175 (56) 505 (50)
Diabetes 521 (25) 1025 (24) 342 (22) 950 (24) 254 (25)
Heart disease 586 (28) 1171 (27) 519 (34) 1074 (28) 164 (16)
Chronic lung disease 415 (20) 931 (22) 351 (23) 883 (23) 112 (11)
Tuberculosis 6 (<1) 19 (<1) 8 (1) 11 (<1) 6 (1)
HIV infection 12 (1) 20 (<1) 5 (<1) 21 (1) 6 (1)
Severe liver disease 37 (2) 82 (2) 32 (2) 72 (2) 15 (1)
Severe kidney impairment 166 (8) 358 (8) 119 (8) 253 (7) 152 (15)
23

RECOVERY Trial- 28天死亡率
•Overall: ↓17%
24

插管：↓36% 用氧：↓18% 沒有用氧
25

26



RECOVERY Trial- Secondary Outcomes
Outcome, n/N (%)
Dexamethasone +
Usual Care
Usual Care Only
Age-Adjusted
RR (95% CI)*
Discharged from hospital
within 28 days
1416/2104 (67.3) 2748/4321 (63.6) 1.10 (1.03-1.17)
Invasive mechanical
ventilation or death†
 Invasive mechanical
ventilation
 Death
462/1780 (26.0)
110/1780 (6.2)
387/1780 (21.7)
1003/3638 (27.6)
298/3638 (8.2)
827/3638 (22.7)
0.93 (0.85-1.01)
0.79 (0.64-0.97)
0.93 (0.84-1.03)
*RR = rate ratio for hospital discharge and risk ratio for receipt of invasive mechanical ventilation or death.
†Analyses exclude those on invasive mechanical ventilation at the time of randomization.
27



CoDex: Dexamethasone to Treat COVID-19–
Related ARDS
• 多中心，隨機，開放式試驗
• 中重度ARDS的COVID-19 病人
• Dexamethasone 20 mg/day for 5 days then
10 mg/day for 5 days or until ICU discharge + SoC
(n = 151) vs
• SOC alone (n = 148)
• 頭28天, mean ventilator-free days:
• Dexamethasone + SoC: 6.6 (95% CI: 5.0-8.2)
• SoC alone: 4.0 (95% CI: 2.9-5.4)
• Difference: 2.26 (95% CI: 0.2-4.38; P = .04)
• No difference in mortality with
dexamethasone + SoC vs SoC alone (56.3% vs
61.5%)
Tomazini. JAMA. 2020;324:1307. NCT04327401.
Standard care
Dexamethasone
28

REMAP-CAP: Effect of Hydrocortisone on
Organ Support-Free Days in Patients With
Severe COVID-19
•多中心，隨機，開放式第四期試驗
•住ICU的嚴重COVID-19病人 (N = 403)
•比較使用固定劑量(hydrocortisone 50或100mg q6h共
七天)、休克劑量(50mg q6h，臨床休克時使用)與未
使用hydrocortisone
1. NCT02735707. 2. The Writing Committee for the REMAP-CAP Investigators. JAMA. 2020;324:1317.
29

REMAP-CAP
• 21天時不需插管或其他器官支持療法天數與死亡率
差異未達統計顯著
30

CAPE-COVID: Low-Dose Hydrocortisone to Treat
COVID-19–Related Acute Respiratory Failure
• 多中心，隨機，雙盲
• 住ICU急性呼吸衰竭的COVID-19 病
人(N=149)
• Hydrocortisone (200 mg/day) vs
placebo
• 因RECOVERY的結果，使此試驗提
早結束
• 在治療失敗兩組無差異
• Hydrocortisone無增加續發性感染
• 菌血症： 6.6% with hydrocortisone vs
11.0% with placebo
Dequin. JAMA. 2020;324:1298. NCT02517489.
Hydrocortisone
Placebo
31

Meta-analysis of Systemic Corticosteroids in
Critically III Patients With COVID-19
WHO REACT Working Group. JAMA. 2020;324:1330.
Trial Location Eligibility Treatment Arms Dose
Outcome
Primary Mortality
DEXA-
COVID 19
Spain
Intubation,
mechanical
ventilation, moderate
to severe ARDS*
Dexamethasone
vs usual care
20 mg/day IV for
5 days, then
10 mg/day IV for
5 days
60-day
mortality
Day 28
CoDEX Brazil
Intubation,
mechanical
ventilation, moderate
to severe ARDS*
Dexamethasone
vs usual care
20 mg/day IV for
5 days, then
10 mg/day IV for
5 days
Ventilator
-free days
Day 28
RECOVERY UK Intubation
Dexamethasone
vs usual care 6 mg/day PO or IV
28-day
mortality
Day 28
CAPE
COVID
France
ICU/intermediate
care unit, O2
(≥6 L/min)
Hydrocortisone vs
placebo
Continuous IV infusion 8-
14 days with tapered
dosing (200 mg/day to
50 mg/day)
21-day
treatmen
t failure
Day 21
32

Meta-analysis of Systemic Corticosteroids in
Critically III Patients With COVID-19
Trial Location Eligibility Treatment Arms Dose
Outcome
Primary Mortality
COVID
STEROID
Denmark O2 (≥10 L/min)
Hydrocortisone vs
placebo
200 mg/
day IV for
7 days
Days alive
without life
support at
Day 28
Day 28
REMAP-
COVID
Australia,
Canada, EU,
New Zealand,
UK, US
Admitted to ICU receiving
high-flow nasal O2 with FIO2
≥0.4 at ≥30 L/min,
noninvasive or invasive
ventilatory support, or
receiving vasopressors
Hydrocortisone vs
usual care
50 mg IV
every
6 hr for 7
days
Composite of
hospital
mortality
and ICU organ
support–free
days to Day 21
Day 28
Steroids
-SARI
China
ICU with PaO2:FIO2 <200
mm Hg on positive pressure
ventilation or high-flow
nasal canulae
>45 L/min
Methylprednisolo
ne vs usual care
40 mg IV
every
12 hr for
5 days
Lower lung
injury score at
Day 7
and Day 14
Day 30
33

Corticosteroids and 28-Day All-Cause Mortality
WHO REACT Working Group. JAMA. 2020;324:1330. 34

Subgroup Analysis of Corticosteroids and 28-Day
All-Cause Mortality
35

Corticosteroids and Serious Adverse Events
36

我國Dexamethasone使用建議
•嚴重肺炎以上(未使用吸氧治療下的SpO2≤94%、需使
用吸氧治療、高流量氧氣或非侵襲性呼吸器、機械式
呼吸器或 ECMO)
•成人劑量：dexamethasone 6mg QD IV/PO，至多10天
•常見副作用有血糖升高與體液滯留，另有小規模研究
顯示可能延遲COVID-19病患病毒清除
37

Remdesivir 瑞德西韋
38

Remdesivir
• nucleoside analogue of ATP
• inhibits SARS-CoV-2 RNA
polymerase by competing with
ATP for inclusion into nascent
RNA
 delayed chain termination
during viral RNA replication
39

Adaptive COVID-19 Treatment Trial (NIAID
ACTT-1)- Study Design
• Multicenter, adaptive, randomized, double-blind, placebo-controlled phase III trial
Adult patients ≥18 yr of age;
hospitalized with symptoms of
COVID-19/SARS-CoV-2 infection and
≥1 of following: radiographic
infiltrates by imaging; SpO2 ≤94% on
room air; requiring supplemental
oxygen; or requiring mechanical
ventilation
(N = 1062)
Remdesivir IV QD
Day 1 200 mg; Day 2-10 100 mg
(n = 541)
Placebo IV QD
(n = 521)
Slide credit: clinicaloptions.com
Beigel. NEJM. 2020;383:1813. NCT04280705.
*Day of recovery is first day patient satisfies 1 of these categories from ordinal scale: 1) hospitalized, not requiring supplemental oxygen,
no longer requires ongoing medical care; 2) not hospitalized, limitation on activities and/or requiring home oxygen; or 3) not hospitalized,
no limitations on activities.
Daily assessment to Day 29 for
time to clinical improvement
while hospitalized;
if discharged, assessments at
Days 15, 22, and 29
Day 10
 Primary endpoint: time to recovery* by Day 29 according to ordinal scale
 Secondary endpoints: treatment-related improvements in 8-point ordinal scale at Day 15
40

NIAID ACTT-1: Clinical Status Ordinal Scale
Clinical Status
Ordinal Scale
Clinical Status Description for Assessment
1 Not hospitalized, no limitations on activities
2 Not hospitalized, limitation on activities, and/or requiring home oxygen
3 Hospitalized, not requiring supplemental oxygen and no longer requires ongoing
medical care (if hospitalization extended for infection-control purposes)
4 Hospitalized, not requiring supplemental oxygen; requiring ongoing medical care
(COVID-19 related or otherwise)
5 Hospitalized, requiring supplemental oxygen
6 Hospitalized, on noninvasive ventilation or high-flow oxygen devices
7 Hospitalized, on invasive mechanical ventilation or ECMO
8 Death
Beigel. NEJM. 2020;383:1813. 41

NIAID ACTT-1: Baseline Characteristics
Characteristic
All
(N = 1062)
Remdesivir
(n = 541)
Placebo
(n = 521)
Mean age, yr (SD) 58.9 (15.0) 58.6 (14.6) 59.2 (15.4)
Male sex, n (%) 684 (64.4) 352 (65.1) 332 (63.7)
Median time from symptom onset to
randomization, days* (IQR)
9 (6-12) 9 (6-12) 9 (7-13)
Number of comorbidities, n/N (%)*
 0
 1
 ≥2
194/1048 (18.5)
275/1048 (26.2)
579/1048 (55.2)
97/531 (18.3)
138/531 (26.0)
296/531 (55.7)
97/517 (18.8)
137/517 (26.5)
238/517 (54.7)
Comorbidities, n/N (%)
 Hypertension
 Obesity
 Type 2 diabetes
533/1051 (50.7)
476/1049 (45.4)
322/1051 (30.6)
269/532 (50.6)
242/531 (45.6)
164/531 (30.8)
264/519 (50.9)
234/518 (45.2)
158/519 (30.4)
*Data were missing for 3 patients; coexisting conditions data were missing for 11 patients and were incomplete for 3 patients.
Beigel. NEJM. 2020;383:1813. 42

• Serious AEs: 51.3% with remdesivir and 57.2% with placebo
• No deaths related to treatment; most common nonserious AEs
occurring in ≥5% of all patients included decreased GFR, decreased
hemoglobin, decreased lymphocyte count, and anemia
NIAID ACTT-1: Efficacy and Safety Summary
Outcome
Remdesivir
(n = 541)
Placebo
(n = 521)
RR/HR (95% CI)* P Value
Median recovery time, days 10 15 1.29 (1.12-1.49) <.001
Mortality by 15 days, %† 6.7 11.9 0.55 (0.36-0.83) NR
*Recovery rate ratio for recovery time and HR for mortality calculated by stratified Cox model. †Kaplan-Meier estimate.
Beigel. NEJM. 2020;383:1813. 43


NIAID ACTT-1: Time to Recovery
Beigel. NEJM. 2020;383:1813. 44

NIAID ACTT-1: Time to Recovery
Beigel. NEJM. 2020;383:1813.
45

NIAID ACTT-1: Subgroup Analysis of Time to Recovery
Beigel. NEJM. 2020;383:1813.
46

SIMPLE-Severe Study:
Remdesivir in Patients With Severe COVID-19
• 多中心，隨機，開放式三期試驗
Hospitalized patients ≥12 yr of age
with SARS-CoV-2 infection confirmed
in last 4 days, SpO2 ≤94% while
breathing ambient air or receiving
supplemental oxygen, and radiologic
evidence of pneumonia
(N = 397)
Remdesivir IV QD
Day 1 200 mg; Days 2-10 100 mg
(n = 197)
Goldman. NEJM. 2020;383:1827. NCT04292899.
Remdesivir IV QD
Day 1 200 mg; Days 2-5 100 mg
(n = 200)
 校正收案時疾病嚴重度後，臨床改善率並無統計差異
47

SIMPLE-Moderate Study:
Remdesivir in Patients With Moderate COVID-19
• Primary endpoint: improvement on 7-point ordinal scale on Day 11
• Secondary endpoint: treatment-emergent adverse events
Patients ≥12 yr of age;
hospitalized with SARS-CoV-2
infection confirmed by RT-PCR;
radiographic infiltrates by
imaging; SpO2 >94% on room air
(N = 584)
Remdesivir IV QD
Day 1 200 mg; Days 2-5 100 mg
(n = 191)
Standard of Care
(n = 200)
Spinner. JAMA. 2020;324:1048. NCT04292730.
Remdesivir IV QD
Day 1 200 mg; Days 2-10 100 mg
(n = 193)
48

SIMPLE-Moderate Study:
Remdesivir in Patients With Moderate COVID-19
• Patients receiving 5-day remdesivir were 65% more
likely to have clinical improvement at Day 11 vs SoC
alone (OR: 1.65; 95% CI: 1.09-2.48; P = .02)
• 10-day remdesivir vs SoC alone: (No OR reported; P = .18)
Clinical Efficacy at Day 11, n (%)
Remdesivir 5-Day
(n = 191)
Remdesivir 10-Day
(n = 193)
SoC
(n = 200)
≥2-point improvement on ordinal scale 134 (70) 126 (65) 121 (61)
Recovery 132 (68) 141 (74) 128 (64)
Requiring any oxygen support 12 (6) 13 (7) 22 (11)
Death 0 2 (1) 4 (2)
Spinner. JAMA. 2020;324:1048. NCT04292730. 49


Study 5773 and Study 5807:
Variables Associated With Odds of Recovery/Death
• GS-US-540–5773: remdesivir-cohort
• GS-US-540–5807: non-remdesivir-cohort
Olender. Clin Infect Dis. 2020;[Epub].
50

GS-US-540-5773: Remdesivir for 5 vs 10 Days for
Hospitalized Patients With Severe COVID-19
• Primary endpoint: time to clinical improvement (≥2-point improvement from BL on 7-point ordinal
scale) at Day 14, time to all-cause mortality at Day 14
• 10-day vs 5-day OR for clinical improvement at Day 14: 0.75 (95% CI: 0.51-1.12)1
• Current multivariate analysis* assessed risk factors for clinical improvement and all-cause mortality in
combined population (5-day and 10-day dosing)2
Adults hospitalized with severe
COVID-19; positive SARS-CoV-2
RT-PCR
<4 days prior to enrolment; SpO2
≤94% on room air; pulmonary
infiltrates on radiograph
(N = 397)
Remdesivir
200 mg IV loading dose; 100 mg IV QD
Remdesivir
200 mg IV loading dose; 100 mg IV QD
1. Remdesivir PI. Updated February 2021. 2. Marks. IAS COVID-19. Abstr 11803.
Day 5 Day 10
*Competing risk analysis, where death is competing risk; remdesivir treatment duration and all risk factors as covariates.
Supportive therapy at clinician discretion
51

BL O2: Low-flow O2/room air vs IMV/HFNC/NIPPV
Age, yr: <65 vs ≥65
Race: Black vs Asian
Race: White vs Asian
Region: Outside Italy vs Italy
Concomitant biologic medication*: No vs Yes
Treatment duration: RDV 5 days vs RDV 10 days
GS-US-540-5773: Baseline Characteristics Associated
With Clinical Improvement
Marks. IAS COVID-19. Abstr 11803.
Risk Factor: Subgroups HR (95% CI) P Value
2.16 (1.50-3.10) <.0001
1.93 (1.46-2.55) <.0001
3.80 (2.28-6.35) <.0001
2.45 (1.60-3.76) <.0001
1.59 (1.07-2.37) .0225
2.70 (1.49-4.88) .0010
1.12 (0.92-1.55) .1822
*Including IFN, plasma, sarilumab, siltuximab, tocilizumab
taken ≥1 day prior or any time during RDV therapy.
No Improvement Improved
0.1 1 10
HR (95% CI)

GS-US-540-5773: Baseline Characteristics Associated
With All-Cause Mortality
Marks. IAS COVID-19. Abstr 11803.
BL O2: IMV/HFNC/NIPPV vs Low-flow O2/room air
COPD: Yes vs No
Age, yr: ≥65 vs <65
Treatment duration: RDV 5 days vs RDV 10 days
Risk Factor: Subgroups HR (95% CI) P Value
5.47 (2.74-10.90) <.0001
3.41 (1.30-8.94) .0125
2.30 (1.18-4.47) .0139
0.97 (0.53-1.78) .9215
Decreased risk Increased risk
0.1 1 10
HR (95% CI)

Efficacy
follow-up
28天時因COVID-19住院或全死因死亡率下降87%(0.7% vs 5.3%, p=0.008)
因COVID-19就診與全死因死亡率亦下降81% (1.6% vs 8.6%, p=0.002)
兩組第七天時鼻咽病毒量並無顯著差異
PINETREE: Remdesivir for Nonhospitalized,
High-Risk Individuals With COVID-19
Nonhospitalized, high-
risk individuals with PCR-
confirmed COVID-19 for
≤4 days and presence of
symptoms for ≤7 days
(N = 584*)
Remdesivir 200 mg IV
(n = 279 )
Placebo
(n = 283 )
Gottlieb, R.L., et al., Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. 2021
多中心，隨機，雙盲三期試驗
Day 1 Days 2 and 3 Day 28
Remdesivir 100 mg IV x 2 days
(n = 279 )
Placebo
(n = 283 )
*Study enrollment was terminated early for administrative reasons (slowing enrollment); 562
patients received ≥1 dose of study drug.
54

我國Remdesivir使用建議-1
• 未使用氧氣且於發病七天內之≥12歲且體重≥40公斤
病患
• 具以下任一風險因子
• 年齡 65歲、糖尿病、慢性腎病、心血管疾病 (含高血
壓 )、慢性肺疾、 BMI≥25 (或 12-17歲兒童青少年 BMI
超過同齡85%)、懷孕、其他影響免疫功能之疾病或已
知重症風險因子
• 成人劑量：200mg IVD D1，100mg IVD D2–3
55

我國Remdesivir使用建議-2
• 嚴重肺炎以上(未使用吸氧治療下的SpO2≤94%、需
使用吸氧治療、高流量氧氣或非侵襲性呼吸器但未
插管病患)
• 成人劑量：200mg IVD D1，100mg IVD D2–5
• 孩童劑量：5mg/kg IVD D1 2.5mg/kg IVD D2–5
• 常見副作用有肝功能上升，藥物交互作用
56

Paxlovid(Nirmatrelvir+Ritonavir)
57

Nirmatrelvir (PF-07321332)
• 口服
• protease inhibitor
• 加上Ritonavir使藥物
濃度增加
• 動物試驗有效下降
SARS-CoV-2病毒
Owen. Science. 2021;[Epub]. 58

•隨機，雙盲三期試驗
• Primary endpoints: percentage of hospitalizations and/or deaths by Day 28
• Secondar endpoints: adverse events
Day 1
Adults with laboratory-
confirmed SARS-CoV-2
(N = 3000)*
Nirmatrelvir + RTV
Q12H
Placebo
Q12H
Follow-up
*Anticipated enrollment; had ≥1 characteristic or comorbidity associated
with increased risk of developing severe illness from COVID-19.
EPIC-HR: Nirmatrelvir + RTV for
Nonhospitalized Patients With COVID-19
Day 28
Day 5 Wk 24
NCT04960202.
Stratified by time since
onset of signs/symptoms
59

Phase III EPIC-HR: Day 28 Interim Efficacy
Analysis
• 非住院，有風險因子的輕中度COVID-19患者，在出
現症狀的3天內服用 nirmatrelvir + RTV Q12H * 5 days
可減少89% (P = .001)住院或死亡
Pfizer press release. November 5, 2021. Data not peer reviewed.
Started By Day 3 Started By Day 5
Outcome
Nirmatrelvir + RTV
(n = 389)
Placebo
(n = 385)
P
Value
Nirmatrelvir + RTV
(n = 607)
Placebo
(n = 612)
P Value
Hospitalization
or death, n (%)
3 (0.8) 27 (7.0) <.0001 6 (1.0) 41 (6.7) <.0001
Deaths, n (%) 0 7 (1.8) <.0001 0 10 (1.6) <.0001
60

FDA EUA for Nirmatrelvir + Ritonavir
• 在輕中度的成人或≥12歲且體重≥ 40公斤的兒童
COVID-19患者，PCR(+)，同時有重症因子
• 症狀出現的5天內服用
• 300 mg nirmatrelvir (150 mg tablets*2) + 100 mg
ritonavir (100 mg tablet*1) Q12H * 5 days
61

Molnupiravir (MK-4822) 莫納皮拉韋
62

Molnupiravir
• 針對RNA依賴性RNA聚合酶(RdRp)，其會藉由體內
代謝而活化，在藥物進入細胞後，會轉化為類似
RNA的組成單位(RNA-like building blocks)抑制病毒複
製
• 倉鼠實驗顯示，於暴露SARS-CoV-2前或後12小時給
予MK-4822，可抑制病毒複製
63

Day 1
 MOVe-IN and MOVe-OUT: randomized, placebo-controlled, double-blind phase II/III trials1-4
confirmed SARS-CoV-2*
(N = 304, phase II1,3,4)
(N = 1850, phase III2,3,4)
Molnupiravir 200 mg Q12H
Placebo Q12H
Follow-up period
MOVe-IN/MOVe-OUT: Molnupiravir for
Hospitalized/Nonhospitalized Patients With COVID-19
Day 29
Day 5 Wk 28
1. NCT04575584. 2. NCT04575597. 3. Strizki. IDWeek 2021. Abstr P511. 4. Grobler. IDWeek 2021. Abstr P543.
Stratified by time since onset of
signs/symptoms and risk for
severe COVID-19
• MOVe-IN: hospitalized adults with signs/symptoms of COVID-19 and symptom onset within previous 10 days
• MOVe-OUT: nonhospitalized adults with signs/symptoms of COVID-19, increased risk of severe illness from
COVID-19, and symptom onset within previous 7 days.
64

MOVe-IN/MOVe-OUT: Molnupiravir Antiviral
Activity
1. Strizki. IDWeek 2021. Abstr P511. 2. Grobler. IDWeek 2021. Abstr P543. 3. Sheahan. Sci Transl Med.
2020;12:eabb5883. 4. Agostini. J Virol. 2019;93:e01348. 5. Szemiel. PLoS Pathog. 2021;17:e1009929.
6. Kabinger. Nat Struct Mol Biol. 2021;28:740. 7. Gordon. J Biol Chem. 2021;297:100770.
Antiviral Potency of NHC Against
SARS-CoV-2 Variants
WA1
(USA)
B.1.1.7
(Alpha)
B.1.351
(Beta)
P.1
(Gamma)
B.1.617.2
(Delta)
NHC IC50, µM 1.41 1.59 1.77 1.32 1.68
• In-vitro studies in Vero
E6 cells demonstrated
NHC had equal activity
against variants of
concern2
65

• 非住院，有風險因子的輕中度COVID-19患者，molnupiravir 800
mg Q12H * 5 days下降50%住院或死亡 (P = .001)
 病毒定序結果顯示molnupiravir對Gamma、Delta與Mu變異株均有效果
Phase III MOVe-OUT: Day 29 Interim Efficacy Analysis
Bernal. NEJM. 2021;[Epub]
Outcome
(n = 385)
Placebo
(n = 377)
Hospitalization or death, n (%) 28 (7.3)* 53 (14.1)
Deaths, n (%) 0 8
Any AE, % 35 40
Drug-related AE, % 12 11
Discontinuation due to AE, % 1.3 3.4
*Reduction in risk of hospitalization and/or death was consistent across key subgroups.
66

Phase III MOVe-OUT Additional Data: Final Analysis
• 非住院，有風險因子的輕中度COVID-19患者(1433人)，
molnupiravir 800 mg Q12H * 5 days下降30%住院或死亡 (P = .0218)
 AE profile consistent with the AE profile in the Day 29 interim analysis
 These additional data were presented to FDA’s Antimicrobial Advisory Committee, and committee
voted 13-10 that the known benefits outweigh potential risks
 Molnupiravir has been authorized for use in the United Kingdom and is being reviewed by the EMA
Bernal. NEJM. 2021;[Epub].
Merck press release. November 30, 2021. Data not peer reviewed.
gov.uk/government/news/first-oral-antiviral-for-covid-19-lagevrio-molnupiravir-approved-by-mhra
Outcome
(n = 709)
Placebo
(n = 699)
Hospitalization or death, n (%) 48 (6.8) 68 (9.7)
Deaths, n (%) 1 9
67

FDA EUA for Molnupiravir
• 在輕中度的成人COVID-19患者，PCR(+)，同時有重
症因子
• 症狀出現的5天內服用
• 800 mg molnupiravir (200 mg tablets*4) Q12H * 5 days
68

Anti–SARS-CoV-2 mAbs
抗 SARS-CoV-2單株抗體
70

BLAZE-1: Impact of Bamlanivimab Plus Etesevimab
on Mild or Moderate COVID-19 Infection
• 隨機，雙盲三期試驗
• 輕中度門診COVID-19病患，具風險因子，治療前3天內PCR(+) (N =
1035)
• Patients recruited had ≥1 risk factor for severe COVID-19 (≥65 yr of age,
BMI ≥35, or 1 relevant comorbidity)
Outcome
Bamlanivimab plus Etesevimab
(N = 518)
Placebo
(n = 517)
Relative Risk Difference
P-Value
Day 29 hospitalization or death
from any cause, n (%)
11 (2.1) 36 (7.0)
70%
p<0.001
Day 29 death from any cause, n (%) 0 10* (1.9)
Dougan. NEJM. 2021; 385:1382.
*9 deaths were designated as COVID-19—related
71

Casirivimab + Imdevimab to Treat
Nonhospitalized Patients With COVID-19
• 隨機，雙盲一-三期試驗1-3
• 第7天病毒量變化casirivimab +
imdevimab vs placebo (n = 524)3
• 高病毒量的病人(>107
copies/mL): -0.68 log10
copies/mL(P <.0001)
• 所有測的到病毒量的病人: -
0.36 log10 copies/mL (P = .0003)
• 在第29天，減少57%因COVID-19就
醫 (N = 799)3
• 2.8% with casirivimab +
imdevimab vs 6.5% with placebo
(P = .024)
Patients with
laboratory-confirmed
COVID-19 treated in
outpatient setting
(N = 799)
Casirivimab + Imdevimab
8 g IV
Placebo
Casirivimab + Imdevimab
2.4 g IV
1. NCT04425629. 2. Weinreich. NEJM. 2021;384:238. 3. https://investor.regeneron.com/news-releases/news-release-
details/regenerons-covid-19-outpatient-trial-prospectively-demonstrates/. Press release only, not peer reviewed.
• 2020/9/4 一/二試驗期中分析，共275
個病人 patients2; 2020/10/28 二/三試
驗資料共524 個病人
72

Randomized 1:1:1
Stratified by baseline
COVID-19 treatment*
 跨國，隨機，雙盲一-三期試驗
Virologic analysis
Day 7
confirmed SARS-CoV-2
infection, onset of COVID-
19 symptoms within prior
10 days, and hospitalized
for ≤72 hr (N = 1197)†
Casirivimab + Imdevimab 8.0g IV‡
(n = 398)
Casirivimab + Imdevimab for Hospitalized
Patients With COVID-19
• Primary virologic endpoint: change in viral load from baseline to Day 7 in seronegative patients
• Primary clinical endpoints: death or mechanical ventilation by Day 29, all-cause mortality, safety
Casirivimab + Imdevimab 2.4g IV‡
(n = 406)
*Stratification: baseline antiviral only (remdesivir) or on no COVID-19 treatments or on corticosteroids or on combination therapy
(remdesivir + corticosteroids). †Study terminated early for low enrollment; modified full analysis set includes pooled cohorts on low flow or
no supplemental oxygen and 2.4 g or 8.0 g dose (n = 804). ‡Single dose coadministered on Day 1 in addition to SoC.
Day 1
Follow-up
Safety analysis
Day 57
Clinical analysis
Day 29
Placebo
(n = 393)
Mylonakis. IDWeek 2021. Abstr LB4.
73

Patients With COVID-19: Virologic Efficacy
• 在血清學陰性病人，第7天病毒量 (LS mean change
-0.28 log10 copies/mL; SE 0.12; P = .017)
Mylonakis. IDWeek 2021. Abstr LB4. 74

Patients With COVID-19: Clinical Efficacy
• Patients Hospitalized With Low Flow/No Supplemental Oxygen
Mylonakis. IDWeek 2021. Abstr LB4.
75

我國複合式抗SARS-CoV-2單株抗體使用建議
• Casirivimab + imdevimab 或 Bamlanivimab + etesevimab
• 未使用氧氣且於發病十天內之≥12歲且體重≥40公斤病患
• 具以下任一風險因子
• 年齡 65歲、糖尿病、慢性腎病、心血管疾病 (含高血壓 )、
慢性肺疾、 BMI≥25 (或 12-17歲兒童青少年 BMI 超過同齡
85%)、懷孕、其他影響免疫功能之疾病或已知重症風險因
子
• 劑量： 600mg casirivimab + 600mg imdevimab 或 700mg
bamlanivimab + 1400mg etesevimab，單次靜脈注射
76

單株抗體對SARS-CoV-2變異株效果實證
Casirivimab +
Imdevimab
Bamlanivimab +
Etesevimab
Sotrovimab Tixagevimab +
cilgavimab
Regdanvimab
Alpha O O O O O
Beta O X O O X
Gamma O X O O X
Delta O O O O O
Delta + O X O O O
Epsilon O O O O O
Lota O O O O O
Kappa O O O O O
Mu O X O O NA
Omicron X X O X X
註： O 有效； X 無效 (unlikely to be active, >100 fold reduction in susceptibility of authentic or pseudovirus；NA表無資料
77

JAK Inhibitors
78

JAK1/2 Inhibitors
Stebbing. EMBO Mol Med. 2020;12:e12697. Slide credit: clinicaloptions.com
79

Baricitinib
• DMARD for rheumatoid arthritis
• 動物試驗
SARS-CoV-2 + Baricitinib
+
Baricitinib Treatment Results
↓ Inflammatory cytokines and chemokines
↓ Neutrophil and macrophage recruitment
↓ NETosis activity
↓ Activated T-cells
Preserved innate viral responses
No change in viral shedding
Hoang. Cell. 2021;184:460. 80

NIAID ACTT-2: Baricitinib + Remdesivir vs Remdesivir
in Hospitalized Patients With Severe COVID-19
• 多中心，隨機，雙盲三期試驗
hospitalized with confirmed
SARS-CoV-2 infection and
≥1 of following: radiographic
infiltrates by imaging, SpO2 ≤94%
on room air, requiring
supplemental oxygen, or
requiring mechanical ventilation
(N = 1034)
Baricitinib PO* + Remdesivir IV QD†
(n = 515)
Placebo PO + Remdesivir IV QD†
(n = 518)
Kalil. NEJM. 2021;384:795.
Daily assessment to Day 29 for
time to clinical improvement
while hospitalized;
if discharged, assessments at
Days 15, 22, and 29
 可加速臨床改善約一天(P=0.03)
*4 mg administered for duration of hospitalization, up to 14 days.
†200 mg on Day 1 followed by 100 mg on Days 2-10.
81

 跨國，隨機，雙盲三期試驗1
Day 14
Adults ≥18 yr of age with RT-
PCR–confirmed SARS-CoV-2
infection requiring invasive
mechanical ventilation or
ECMO and elevation of ≥1
serum inflammatory marker1,2
(N = 101)
Placebo + SoC*
(n = 50 )
COV-BARRIER Addendum Study: Baricitinib + Standard
of Care for Hospitalized Adults With COVID-19
Baricitinib 4 mg + SoC*
(n = 51 )
1. Ely. IDWeek 2021. Abstr LB3. 2. ClinicalTrials.gov. NCT04421027.
*Included baseline systemic corticosteroid use in 86% of participants.
Day 1
Prespecified exploratory
analyses
Day 60
Day 28
Outcome by Day 28 Baricitinib + SoC (n = 51) Placebo + SoC (n = 50) P Value†
All-cause mortality, n (%)
 KM estimates, (95% CI)
20 (39.2)
40.6 (25.8-59.7)
29 (58.0)
59.0 (41.1-77.7) .03
 HR (95% CI) 0.54 (0.31-0.96)
Mean ventilator-free days (SD) 8.1 (10.2) 5.5 (8.4) .21
Mean duration of hospitalization, days (SD) 23.7 (7.1) 26.1 (3.9) .05
82

 跨國，隨機，雙盲三期試驗1
Day 14
Adults ≥18 yr of age with RT-
PCR–confirmed SARS-CoV-2
infection requiring invasive
mechanical ventilation or
ECMO and elevation of ≥1
serum inflammatory marker1,2
(N = 101)
Placebo + SoC*
(n = 761 )
COV-BARRIER Study: Baricitinib + Standard of Care for
Hospitalized Adults With COVID-19
•28天全死因死亡率下降38.2%(8.1% vs 13.1%)，且效果在收案
時使用高流量氧氣或非侵襲性呼吸器之病患最顯著(HR 0.52,
p=0.007)
Baricitinib 4 mg + SoC*
(n = 764 )
1. Ely. IDWeek 2021. Abstr LB3. 2. ClinicalTrials.gov. NCT04421027.
*Included baseline systemic corticosteroid use in 86% of participants.
Day 1
Prespecified exploratory
analyses
Day 60
Day 28
83

Overall Mortality of Patients Receiving
Baricitinib vs Placebo
Hempel AK, Jevtic SD, Vandersluis S, et al. Baricitinib for hospitalized patients with COVID-19. Science Briefs of the Ontario
COVID-19 Science Advisory Table. 2022;3(53)
84

STOP-COVID trial: Tofacitinib in Patients
Hospitalized with Covid-19 Pneumonia
• 18歲以上住院確診病患，未使用
非侵襲性呼吸器或插管者，住院
三天內隨機分配接受口服
tofacitinib(n=144)(至多14天)或標
準治療(n=145)
• 治療組28天時死亡或插管率下降
37% (18% vs 29%, RR=0.63,
P=0.04)，但死亡率無顯著差異
(2.8% vs 5.5%, HR 0.49, CI 0.15-
1.63)
N Engl J Med 2021;385:406-15. 85

我國JAK Inhibitors(Baricitinib)使用建議
• 使用高流量氧氣或非侵襲性呼吸器但未插管，同時
發炎指數上升 (CRP ≥ 7.5 mg/dL)
• 與dexamethasone，或 dexamethasone + remdesivir
合併使用
• 劑量： 4mg QD PO 14天或至出院
• 無法使用 baricitinib 者，可使用 tofacitinib 10mg BID
PO至多 14天
86

IL-6R Inhibitors
87

Anti–IL-6 Receptor Antibodies
Fu. J Translational Medicine. 2020;18:164. 88

TESEO Cohort: Tocilizumab to Treat Severe COVID-
19 in Italy
• 回溯性世代研究統計179名嚴重肺炎患者使用tocilizumab(皮下或靜脈注射)，相較於365名接
受標準治療者
• Tocilizumab: 8 mg/kg via 2 infusions 12 hr apart or 162 mg SQ in each thigh (324 mg
total) when IV formulation unavailable
• 死亡率較低且達統計顯著（13% vs 20%）
Guarlandi. Lancet Rheumatology. 2020;20:30173.
Cumulative
Probability
Days From Admission
Standard of care
Tocilizumab
Log-rank P = .0023
14
0 1 2 3 4 5 6 7 8 9 10 11 12 13
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Cumulative
Probability
Days From Admission
Standard of care
Tocilizumab
Log-rank P <.0001
14
0 1 2 3 4 5 6 7 8 9 10 11 12 13
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Mechanical Ventilation or Death
(Primary Outcome)
Mechanical Ventilation and Death
89

COVACTA: Tocilizumab vs Placebo
for Severe COVID-19 Pneumonia
 跨國，隨機，雙盲三期試驗
 Other Day 28 endpoints with
tocilizumab vs placebo
‒ Deaths: 19.7% vs 19.4% (P = .94)
‒ Infections: 38.3% vs 40.6%
‒ Serious infections: 21.0% vs
25.9%
 No tocilizumab-associated safety
concerns observed
Rosas. NEJM. 2021;384:1503. NCT04320615.
Adult patients
hospitalized with
severe COVID-19
pneumonia
(N = 438)
Tocilizumab IV + SoC
(n = 294)
Placebo + SoC
(n = 144)
 Primary endpoint: clinical status at Day 28
by 7-category ordinal scale based on need
for intensive care and/or ventilator use,
supplemental oxygen requirements
28天死亡率並無差異(19.7% vs 19.4%)

EMPACTA: Tocilizumab vs Placebo
for COVID-19 Pneumonia
 跨國，隨機，雙盲三期試驗
 Primary endpoint: cumulative
proportion of participants requiring
mechanical ventilation or dying at
Day 28
 Primary endpoint met: proportion
of patients who progressed to
mechanical ventilation or death by
Day 28 was 12.0% in the tocilizumab
arm vs 19.3% in the placebo arm
‒ HR: 0.56 (95% CI: 0.33-0.97; P = .04)
 No difference in time to hospital
discharge, time to improvement in
clinical status, time to clinical failure,
incidence of infections, or mortality
Salama. NEJM. 2021;384:20. NCT04372186.
Adult patients
hospitalized with
COVID-19
pneumonia
(N = 377)
Tocilizumab IV + SoC
(n = 249)
Placebo + SoC
(n = 128)

REMAP-CAP: Enrollment at 113 Sites in 6 Countries
 Randomized, embedded, multifactorial, adaptive platform (REMAP) phase IV trial
Tocilizumab 8 mg/kg (max 800 mg) IV x 1 or 2 doses
(n = 353)
Usual Care
(n = 402)
Sarilumab* 400 mg IV x 1 dose
(n = 48)
Anakinra or interferon β-1a
(n = 62)
Adult patients with
suspected or confirmed
severe COVID-19
admitted to ICU and
receiving organ support
(N = 865)
33% (265/807) of patients received remdesivir. Among those enrolled after RECOVERY results for dexamethasone announced,
93% (610/654) received corticosteroids. *Fewer enrollees due to later on-trial availability of sarilumab (June) vs tocilizumab (April).
REMAP-CAP Investigators. NEJM. 2021;[Epub]. NCT02735707.
 Primary outcome: respiratory and cardiovascular organ support-free days, up to Day 21
 Secondary outcomes: 90-day survival, time to discharge, and ordinal scale improvement
n=401

REMAP-CAP: Tocilizumab, Sarilumab Interim
Results
• 401名入住ICU之確診病患，於入住ICU 24小時內接受tocilizumab 或
sarilumab治療，相較於402名接受標準治療者，21天時無器官衰竭
之天數顯著較長(10 vs 11天vs 0天)，住院死亡率也較低(28% vs 22%
vs 35.8%)
0.2
Primary Outcome:
Organ Support-Free Days
Days
Survival
Cumulative
Proportion
Tocilizumab Sarilumab Usual care
20
0 5 10 15
1.0
0.8
0.6
0.4
0.2
0
Days
Probability
90
0 15 60 75
1.0
0.8
0.6
0.4
0
0.2
30 45
++
+ +
+ + +
+ +
+
+
+ +
+
+ +
+ + +
++
++
+ + +
+
+
+
+ +
+ +
++ ++
++
+ ++ + + +
+
++ +
+ + ++
REMAP-CAP Investigators. NEJM. 2021;[Epub]. 93

 Primary endpoint: all-cause mortality at 28 days
 Secondary endpoints: time to discharge and receipt of mechanical ventilation
 82% of patients received corticosteroids as part of usual care (97% since June 2020)
Randomised Evaluation of COVID-19 Therapy
(RECOVERY) Trial: Study Design
 Multicenter, factorial, randomized, open label, controlled phase III trial
hospitalized with clinical evidence of
progressive COVID-19: SpO2 <92% on
room air or requiring supplemental
oxygen and CRP ≥75 mg/L; within
21 days of initial randomization*
(N = 4116)
Tocilizumab IV† initial dose + optional second dose 12-24 hr later
+ Usual Care‡
(n = 2022)
Usual Care‡
(n = 2094)
Recovery Collaborative Group. Lancet. 2021 May 1;397(10285):1637.
New
*Initially randomized to usual care, LPV/RTV, dexamethasone, hydroxychloroquine, or azithromycin. †Dosing by
weight: 800 mg for patients >90 kg; 600 mg for patients >65 and <90 kg; 400 mg for patients >40 kg and ≤65 kg;
8 mg/kg for patients ≤40 kg. ‡Ventilator support at BL: 46%/45% on no ventilation, 41%/41% receiving noninvasive
ventilation, and 13%/14% receiving invasive mechanical ventilation for tocilizumab/usual care groups, respectively.

RECOVERY: Results for Tocilizumab + Usual Care vs
Usual Care Alone
 Tocilizumab組相較於標準
治療組，28天死亡率較低
(RR 0.86, CI 0.77-0.96)，且
存活出院率較高(RR 1.23,
CI 1.12-1.34)
Recovery Collaborative Group. Lancet. 2021 May 1;397(10285):1637.
Days Since Randomization
Mortality
(
%)
40
30
20
10
0
RR: 0.86 (0.77-0.96)
Log-rank P = .0066 Usual care
Tocilizumab +
usual care
28
0 7 14 21
Patients
at Risk, n
Active
Control
2022
2094
1741
1740
1556
1518
1386
1372
1284
1250

WHO meta-analysis of IL-6R Inhibitors
(tocilizumab/siltuximab/sarilumab) in COVID-19
• 27個隨機對照試驗，共10930名病患
• 使用IL-6抑制劑(tocilizumab/siltuximab/sarilumab)者，
相較於僅使用包括類固醇在內之標準治療，28天死
亡率下降(22% vs 25%, OR 0.86, CI 0.79-0.95)，且使
用呼吸器比例較低(OR 0.72, CI 0.57-0.90)
JAMA. 2021;326(6):499-518. 96

我國Tocilizumab使用建議
• 與dexamethasone合併用於嚴重肺炎以上 (未使用吸氧治
療下 SpO2 94%、需使用吸氧治療、高流量氧氣或非侵
襲性呼吸器、使用機械式呼吸器或ECMO)之病患
• 與 dexamethasone + remdesivir 合併用於未使用吸氧治
療下SpO2 94%、需使用吸氧治療、高流量氧氣或非侵襲
性呼吸器之病患
• 劑量： 8mg/kg(至多 800mg)，單次靜脈注射
97

其它
98

Fluvoxamine
• SSRI(selective serotonin reuptake inhibitor)
• Anti-inflammatory and possible antiviral effects
• TOGETHER trial
• 741名具重症風險門診病患接受fluvoxamine十天治療，
相較於756名接受安慰劑者，28天內前往急診或住院機
率較低(11% vs 16%, RR 0.52-0.88)，且兩組副作用比例
並無差異 Lancet Glob Health 2022;10: e42–51
99

SOF/DCV (sofosbuvir/daclatasvir)
• Anti-HCV direct-acting antivirals
Trial Treatment Arms Endpoint
DDRI (Tehran), N = 66 SOF/DCV + LPV/RTV vs LPV/RTV Time to clinical recovery within 14 days
Abadan, N = 62 SOF/DCV + HCQ vs LPV/RTV + HCQ + RBV Time to hospital discharge
Sari, N = 48 SOF/DCV + RBV vs HCQ ± LPV/RTV Duration of hospitalization
Sadeghi. IAS COVID-19. Abstr 11125.
Study RR (95% CI) Weight*
Abadan
Sari
Tehran
Overall (I-squared = 61.6%)
Test of overall effect = 1: z = 2.34 P = .020
0.5 1 2
Favors SOF/DCV
Favors SoC
1.82 (1.25-2.64)
1.14 (0.96-1.35)
1.32 (1.00-1.73)
1.34 (1.05-1.71)
24.01
43.49
32.50
100.00
100

Convalescent Plasma 恢復期血清
• 統合分析十個隨機對照試驗，共11782名病患使用
結果，恢復期血清無法降低病患死亡風險(RR 1.02,
0.92-1.12)
• Cochrane review：統合分析13 個隨機對照試驗，共
48509名病患資料顯示，對中重度COVID-19病患，
恢復期血清無助於降低病患死亡率或改善呼吸狀況，
但對輕症或無症狀病患，恢復期血清效果尚無明確
證據
JAMA. 2021;325(12):1185-1195.
Cochrane Database Syst Rev, 2021. 5: p. CD013600. 101

我國COVID-19確診病患用藥建議彙整
不需用氧需吸氧治療高流量氧或NIV 插管
降低死亡率，
建議使用
Dexamethasone Dexamethasone Dexamethasone
+ Tocilizumab
+ Baricitinib或
tocilizumab
+ Tocilizumab
Casirivimab + imdevimab 或
Bamlanivimab + etesevimab或
Remdesivir
加速臨床改善，
考慮使用
+ Remdesivir
新型冠狀病毒（SARS-CoV-2）感染臨床處置暫行指引第十五版 102

outline
COVID-19簡介
藥物治療
氧氣治療
103

氧氣使用
• 患者都戴外科口罩
• 開始時機：SpO2 ≤ 94% room air
• 目標：待病人穩定無危急徵候後， SpO2 ≥ 90%
• N/C 5 L/min為上限
• NRM
• HFNO(high flow nasal oxygen)
104

各種呼吸治療造成飛沫傳播的比較
ACEP COVID-19 Field Guide
NIPPV
Nebulizer
Simple mask
Venturi mask
Nasal cannula
HFNO
NRM
105

氧氣使用
• Nasal canula NRM (HFNO) ventilator
• 如果允許，使用 high flow nasal cannula 取代NRM
• 感染病患避免使用 Nebulizer等氣霧式治療，可使用
Dry-powder inhaler或 Metered-dose inhaler MDI
106

插管前的氧氣治療
• 多中心，隨機，開放式試驗
• 有急性缺氧呼吸衰竭，無hypercapnia，併PaO2/FiO2 <300 mm Hg的成人患者 (N = 310)
Frat. NEJM. 2015;372:2185.
HR for Death at 90 Days:
High-flow vs standard: 2.01 (95% CI: 1.01-3.99)
High-flow vs noninvasive: 2.50 (95% CI: 1.31-4.78)
Intubation Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Cumulative
Incidence
of
Intubation
Days Since Enrollment
0 4 8 12 16 20 24 28
P = .17 by log-rank test
Noninvasive ventilation
Standard oxygen
High-flow oxygen
Patients at Risk, n
High-flow oxygen
Standard oxygen
Noninvasive ventilation
106
94
110
68
52
64
67
50
57
67
49
53
65
49
53
65
49
53
65
48
53
65
48
52
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Days Since Enrollment
0 15 30 45 60 72 90
P = .02 by log-rank test
106
94
110
100
84
93
97
81
86
94
77
80
94
74
79
93
73
78
93
72
77
Cumulative
Probability
of
Survival
107

Summary
•依病理生理學原則，
•抗病毒藥劑與抗 SARS-CoV-2單株抗體建議於病程早
期使用
•類固醇與免疫調節劑則於病程晚期併發重症時使用
•適當的氧氣治療可改善症狀及預後，其中高流
量鼻導管（high flow nasal oxygen, HFNO）給氧，
有機會降低插管機率與改善病人預後
108

謝謝聆聽，敬請指教
109

Currently designated variants of concern (VOCs)
WHO lab
el
Pango
lineage
Additional ami
no acid
changes monit
ored°
Earliest
documented
samples
Date of
designation
Impact on
transmissibilit
y
Impact on
immunity
Impact on
severity
Transmissio
n in EU/EEA
Alpha B.1.1.7
+S:484K
+S:452R
United
Kingdom,Sep-
2020
18-Dec-2020
Beta B.1.351 +S:L18F South Africa,
May-2020
18-Dec-2020
Increased (v)
(1)
Increased (v) (2,
3)
Increased (v) (4,
5)
Community
Gamma P.1
+S:681H
Brazil,
Nov-2020
11-Jan-2021
Increased (v)
(6)
Increased (v) (7) Increased (v) (5) Community
Delta
B.1.617.2
+S:417N
+S:484K
India,
Oct-2020
VOI: 4-Apr-2021
VOC: 11-May-
2021
Increased (v)
(8)
Increased (v) (9-
11)
Increased (v) (10,
12)
Community
Omicron* B.1.1.529 +S:R346K
Multiple
countries, Nov-
2021
VUM: 24-Nov-
2021
VOC: 26-Nov-
2021
Unclear (v)
(13-15) a
Increased (v)
(16)
Unclear (v) (17,
18) b
Community
WHO website, official website of the European Union 110

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