please read the two articles and write critique for both of them.
The
n e w e ng l a n d j o u r na l
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Original Article
A Trial of Lopinavir–Ritonavir in Adults
Hospitalized with Severe Covid-19
B. Cao, Y. Wang, D. Wen, W. Liu, Jingli Wang, G. Fan, L. Ruan, B. Song, Y. Cai,
M. Wei, X. Li, J. Xia, N. Chen, J. Xiang, T. Yu, T. Bai, X. Xie, L. Zhang, C. Li,
Y. Yuan, H. Chen, Huadong Li, H. Huang, S. Tu, F. Gong, Y. Liu, Y. Wei, C. Dong,
F. Zhou, X. Gu, J. Xu, Z. Liu, Y. Zhang, Hui Li, L. Shang, K. Wang, K. Li, X. Zhou,
X. Dong, Z. Qu, S. Lu, X. Hu, S. Ruan, S. Luo, J. Wu, L. Peng, F. Cheng, L. Pan,
J. Zou, C. Jia, Juan Wang, X. Liu, S. Wang, X. Wu, Q. Ge, J. He, H. Zhan, F. Qiu,
L. Guo, C. Huang, T. Jaki, F.G. Hayden, P.W. Horby, D. Zhang, and C. Wang
A BS T R AC T
BACKGROUND
No therapeutics have yet been proven effective for the treatment of severe illness
caused by SARS-CoV-2.
METHODS
We conducted a randomized, controlled, open-label trial involving hospitalized
adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory
illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were
breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the
fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly
assigned in a 1:1 ratio to receive either lopinavir–ritonavir (400 mg and 100 mg,
respectively) twice a day for 14 days, in addition to standard care, or standard care
alone. The primary end point was the time to clinical improvement, defined as the
time from randomization to either an improvement of two points on a seven-category
ordinal scale or discharge from the hospital, whichever came first.
The authors’ full names, academic degrees, and affiliations are listed in the
Appendix. Address reprint requests to
Dr. Cao at caobin_ben@163.com, to Dr.
C. Wang at c yh-birm@263.net, or to Dr.
D. Zhang at 1813886398@qq.com.
Drs. Cao, Y. Wang, Wen, W. Liu, Jingli
Wang, Fan, L. Ruan, Song, Cai, and M. Wei
and Drs. D. Zhang and C. Wang contributed equally to this article.
This article was published on March 18,
2020, and last updated on March 20, 2020,
at NEJM.org.
DOI: 10.1056/NEJMoa2001282
Copyright © 2020 Massachusetts Medical Society.
RESULTS
A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent
randomization; 99 were assigned to the lopinavir–ritonavir group, and 100 to the
standard-care group. Treatment with lopinavir–ritonavir was not associated with a
difference from standard care in the time to clinical improvement (hazard ratio for
clinical improvement, 1.24; 95% confidence interval [CI], 0.90 to 1.72). Mortality
at 28 days was similar in the lopinavir–ritonavir group and the standard-care group
(19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In
a modified intention-to-treat analysis, lopinavir–ritonavir led to a median time to
clinical improvement that was shorter by 1 day than that observed with standard
care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were
more common in the lopinavir–ritonavir group, but serious adverse events were
more common in the standard-care group. Lopinavir–ritonavir treatment was
stopped early in 13 patients (13.8%) because of adverse events.
CONCLUSIONS
In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care. Future trials in patients with severe
illness may help to confirm or exclude the possibility of a treatment benefit. (Funded
by Major Projects of National Science and Technology on New Drug Creation and
Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.)
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The
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eginning in December 2019, a novel
coronavirus, designated SARS-CoV-2, has
caused an international outbreak of respiratory illness termed Covid-19. The full spectrum
of Covid-19 ranges from mild, self-limiting respiratory tract illness to severe progressive pneumonia, multiorgan failure, and death.1-4 Thus far,
there are no specific therapeutic agents for coronavirus infections. After the emergence of severe
acute respiratory syndrome (SARS) in 2003, screening of approved drugs identified lopinavir, a
human immunodeficiency virus (HIV) type 1
aspartate protease inhibitor, as having in vitro
inhibitory activity against SARS-CoV, the virus
that causes SARS in humans.5-7 Ritonavir is combined with lopinavir to increase its plasma halflife through the inhibition of cytochrome P450.
An open-label study published in 2004 suggested,
by comparison with a historical control group
that received only ribavirin, that the addition of
lopinavir–ritonavir (400 mg and 100 mg, respectively) to ribavirin reduced the risk of adverse
clinical outcomes (acute respiratory distress syndrome [ARDS] or death) as well as viral load
among patients with SARS.5 However, the lack of
randomization and a contemporary control group
and the concomitant use of glucocorticoids and
ribavirin in that study made the effect of lopinavir–ritonavir difficult to assess. Similarly, lopinavir has activity, both in vitro8 and in an animal
model,9 against Middle East respiratory syndrome
coronavirus (MERS-CoV), and case reports have
suggested that the combination of lopinavir–ritonavir with ribavirin and interferon alfa resulted in
virologic clearance and survival.10-12 However, because convincing data about the efficacy of this
approach in humans are lacking,12 a clinical trial
(with recombinant interferon beta-1b) for MERS
is currently under way (ClinicalTrials.gov number,
NCT02845843).13-15
To evaluate the efficacy and safety of oral
lopinavir–ritonavir for SARS-CoV-2 infection, we
conducted a randomized, controlled, open-label
trial, LOTUS China (Lopinavir Trial for Suppression of SARS-Cov-2 in China), in adult patients
hospitalized with Covid-19.
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Tec or Sansure Biotech) for SARS-CoV-2 in a respiratory tract sample tested by the local Center
for Disease Control (CDC) or by a designated diagnostic laboratory. Male and nonpregnant female
patients 18 years of age or older were eligible if
they had a diagnostic specimen that was positive
on RT-PCR, had pneumonia confirmed by chest
imaging, and had an oxygen saturation (Sao2) of
94% or less while they were breathing ambient
air or a ratio of the partial pressure of oxygen
(Pao2) to the fraction of inspired oxygen (Fio2)
(Pao2:Fio2) at or below 300 mg Hg. Exclusion
criteria included a physician decision that involvement in the trial was not in the patient’s best interest, presence of any condition that would not
allow the protocol to be followed safely, known
allergy or hypersensitivity to lopinavir–ritonavir,
known severe liver disease (e.g., cirrhosis, with
an alanine aminotransferase level >5× the upper
limit of the normal range or an aspartate aminotransferase level >5× the upper limit of the normal range), use of medications that are contraindicated with lopinavir–ritonavir and that could
not be replaced or stopped during the trial period (see the Supplementary Appendix, available
with the full text of this article at NEJM.org);
pregnancy or breast-feeding, or known HIV infection, because of concerns about the development
of resistance to lopinavir–ritonavir if used without
combining with other antiretrovirals. Patients who
were unable to swallow received lopinavir–ritonavir
through a nasogastric tube.
Trial Design and Oversight
This was an open-label, individually randomized,
controlled trial conducted from January 18, 2020,
through February 3, 2020 (the date of enrollment of the last patient), at Jin Yin-Tan Hospital,
Wuhan, Hubei Province, China. Because of the
emergency nature of the trial, placebos of lopinavir–ritonavir were not prepared. Eligible patients were randomly assigned in a 1:1 ratio to
receive either lopinavir–ritonavir (400 mg and
100 mg, orally; freely provided by the national
health authority) twice daily, plus standard care,
or standard care alone, for 14 days. Standard care
comprised, as necessary, supplemental oxygen,
noninvasive and invasive ventilation, antibiotic
Me thods
agents, vasopressor support, renal-replacement
Patients
therapy, and extracorporeal membrane oxygenPatients were assessed for eligibility on the basis ation (ECMO). To balance the distribution of oxyof a positive reverse-transcriptase–polymerase- gen support between the two groups as an indicachain-reaction (RT-PCR) assay (Shanghai ZJ Bio- tor of severity of respiratory failure, randomization
2
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Trial of Lopinavir–Ritonavir in Severe Covid-19
was stratified on the basis of respiratory support
methods at the time of enrollment: no oxygen
support or oxygen support with nasal duct or
mask, or high-flow oxygen, noninvasive ventilation, or invasive ventilation including ECMO. The
permuted block (four patients per block) randomization sequence, including stratification, was
prepared by a statistician not involved in the trial,
using SAS software, version 9.4 (SAS Institute). To
minimize allocation bias, we performed allocation
concealment with an interactive Web-based response system until randomization was finished
on the system through a computer or phone.
The trial was approved by the institutional
review board of Jin Yin-Tan Hospital. Written
informed consent was obtained from all patients
or from the patient’s legal representative if the
patient was too unwell to provide consent. The
trial was conducted in accordance with the principles of the Declaration of Helsinki and the
Good Clinical Practice guidelines of the International Conference on Harmonisation. The authors
were responsible for designing the trial and for
compiling and analyzing the data. The authors
vouch for the completeness and accuracy of the
data and for the adherence of the trial to the protocol. Full details about the trial design are provided in the protocol, available at NEJM.org.
Clinical and Laboratory Monitoring
tained for all 199 patients who were still alive at
every time point. Sampling did not stop when a
swab at a given time point was negative. Baseline
throat swabs were tested for detection of E gene,
RdRp gene, and N gene, and samples on the subsequent visits were quantitatively and qualitatively
detected for E gene. Clinical data were recorded on
paper case record forms and then double-entered
into an electronic database and validated by trial
staff.
Outcome Measures
The primary end point was the time to clinical
improvement, defined as the time from randomization to an improvement of two points (from
the status at randomization) on a seven-category
ordinal scale or live discharge from the hospital,
whichever came first. The end point of clinical
improvement was used in our previous influenza
study17 and was also recommended by the WHO
R&D Blueprint expert group.18 Ordinal scales have
been used as end points in clinical trials in patients hospitalized with severe influenza.16-19 The
seven-category ordinal scale consisted of the following categories: 1, not hospitalized with resumption of normal activities; 2, not hospitalized,
but unable to resume normal activities; 3, hospitalized, not requiring supplemental oxygen; 4,
hospitalized, requiring supplemental oxygen; 5,
hospitalized, requiring nasal high-flow oxygen
therapy, noninvasive mechanical ventilation, or
both; 6, hospitalized, requiring ECMO, invasive
mechanical ventilation, or both; and 7, death.
Other clinical outcomes included clinical status as assessed with the seven-category ordinal
scale on days 7 and 14, mortality at day 28, the
duration of mechanical ventilation, the duration
of hospitalization in survivors, and the time (in
days) from treatment initiation to death. Virologic
measures included the proportions with viral
RNA detection over time and viral RNA titer areaunder-the-curve (AUC) measurements.
Safety outcomes included adverse events that
occurred during treatment, serious adverse events,
and premature discontinuation of treatment. Adverse events were classified according to the
National Cancer Institute Common Terminology
Criteria for Adverse Events, version 4.0.
Patients were assessed once daily by trained nurses
using diary cards that captured data on a sevencategory ordinal scale and on safety from day 0
to day 28, hospital discharge, or death. Safety was
monitored by the Good Clinical Practice office
from Jin Yin-tan Hospital. Other clinical data
were recorded using the WHO-ISARIC (World
Health Organization–International Severe Acute
Respiratory and Emerging Infections Consortium) case record form (https://isaric.tghn.org).16
Serial oropharyngeal swab samples were obtained on day 1 (before lopinavir–ritonavir was
administered) and on days 5, 10, 14, 21, and 28
until discharge or death had occurred and were
tested at Teddy Clinical Research Laboratory
(Tigermed–DiAn Joint Venture), using quantitative real-time RT-PCR (see the Supplementary Appendix). RNA was extracted from clinical samples
with the MagNA Pure 96 system, detected and
quantified by Cobas z480 qPCR (Roche), with the Statistical Analysis
use of LightMix Modular SARS-CoV-2 (COVID19) The trial was initiated in rapid response to the
assays (TIB MOBIOL). These samples were ob- Covid-19 public health emergency, at which time
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3
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there was very limited information about clinical
outcomes in hospitalized patients with Covid-19.
The original total sample size was set at 160,
since it would provide the trial with 80% power
to detect a difference, at a two-sided significance level of α = 0.05, of 8 days in the median
time to clinical improvement between the two
groups, assuming that the median time in the
standard-care group was 20 days and that 75%
of the patients would reach clinical improvement. The planned enrollment of 160 patients in
the trial occurred quickly, and the assessment at
that point was that the trial was underpowered;
thus, a decision was made to continue enrollment by investigators. Subsequently, when another agent (remdesivir) became available for
clinical trials, we decided to suspend enrollment
in this trial.
Primary efficacy analysis was on an intention-to-treat basis and included all the patients
who had undergone randomization. The time to
clinical improvement was assessed after all patients had reached day 28, with failure to reach
clinical improvement or death before day 28
considered as right-censored at day 28 (rightcensoring occurs when an event may have occurred after the last time a person was under
observation, but the specific timing of the event
is unknown). The time to clinical improvement
was portrayed by Kaplan–Meier plot and compared with a log-rank test. Hazard ratios with
95% confidence intervals were calculated by
means of the Cox proportional-hazards model.
Five patients who had been assigned to the lopinavir–ritonavir group did not receive any doses
(three of them died within 24 hours) but were
included in the intention-to-treat analysis, since
no reciprocal removals occurred in the standardcare group. A modified intention-to-treat analysis
that excluded three early deaths was also performed. Post hoc analyses include subgroup analysis for National Early Warning Score 2 (NEWS2)19
of 5 or below or greater than 5 and those who
underwent randomization up to 12 days or more
than 12 days after the onset of illness.
Because the statistical analysis plan did not
include a provision for correcting for multiplicity
in tests for secondary or other outcomes, results
are reported as point estimates and 95% confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity, so
4
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the intervals should not be used to infer definitive
treatment effects for secondary outcomes. Safety
analyses were based on the patients’ actual treatment exposure. Statistical analyses were conducted with SAS software, version 9.4 (SAS Institute).
R e sult s
Patients
Of the 199 patients who underwent randomization, 99 patients were assigned to receive lopinavir–ritonavir and 100 patients to standard care
alone. Of the 99 patients assigned to receive lopinavir–ritonavir, 94 (94.9%) received treatment as
assigned (Fig. 1). In the lopinavir–ritonavir group,
5 patients did not receive any doses of lopinavir–
ritonavir: 3 because of early death within 24 hours
after randomization and 2 others because the attending physician refused to prescribe lopinavir–
ritonavir after randomization.
The median age of patients was 58 years (interquartile range [IQR], 49 to 68 years), and 60.3%
of the patients were men (Table 1). The median
interval time between symptom onset and randomization was 13 days (IQR, 11 to 16 days) (Table 2). There were no important between-group
differences in demographic characteristics, baseline laboratory test results, distribution of ordinal
scale scores, or NEWS2 scores at enrollment.
During the trial, systemic glucocorticoids were
administered in 33.0% of the patients in the
lopinavir–ritonavir group and in 35.7% of those
in the standard-care group.
Primary Outcome
Patients assigned to lopinavir–ritonavir did not
have a time to clinical improvement different from
that of patients assigned to standard care alone in
the intention-to-treat population (median, 16 day
vs. 16 days; hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to
1.85; P = 0.09) (Fig. 2). In the modified intentionto-treat population, the median time to clinical
improvement was 15 days in the lopinavir–ritonavir group, as compared with 16 days in the
standard-care group (hazard ratio, 1.39; 95% CI,
1.00 to 1.91) (Table S1 and Fig. S1 in the Supplementary Appendix). In the intention-to-treat population, lopinavir–ritonavir treatment within 12
days after the onset of symptoms was not found
to be associated with shorter time to clinical
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Trial of Lopinavir–Ritonavir in Severe Covid-19
improvement (hazard ratio, 1.25; 95% CI, 0.77
to 2.05); similar results were found regarding
later treatment with lopinavir–ritonavir (hazard
ratio, 1.30; 95% CI, 0.84 to 1.99) (Fig. S2A and
S2B). No significant differences were observed
when the time to clinical improvement was assessed by NEWS2 score at entry in the intention-to-treat population (Fig. S3A and S3B). In
addition, when the time to clinical deterioration (defined as a one-category increase on the
seven-category scale) was compared between the
two groups, no difference was observed (hazard
ratio for clinical deterioration, 1.01; 95% CI,
0.76 to 1.34) (Fig. S4).
care group for either the intention-to-treat population (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7) or the modified
intention-to treat population (16.7% vs. 25.0%;
difference, −8.3 percentage points; 95% CI, −19.6
to 3.0) (Table 3).
Patients in the lopinavir–ritonavir group had
a shorter stay in the intensive care unit (ICU)
than those in the standard-care group (median,
6 days vs. 11 days; difference, −5 days; 95% CI,
−9 to 0), and the duration from randomization
to hospital discharge was numerically shorter
(median, 12 days vs. 14 days; difference, 1 day;
95% CI, 0 to 3]). In addition, the percentage of
patients with clinical improvement at day 14 was
Secondary Outcomes
higher in the lopinavir–ritonavir group than in
The 28-day mortality was numerically lower in the the standard-care group (45.5% vs. 30.0%; diflopinavir–ritonavir group than in the standard- ference, 15.5 percentage points; 95% CI, 2.2 to
357 Participants were assessed
for eligibility
158 Were excluded
113 Did not meet eligibility criteria
31 Did not have family consent
14 Had other reason
199 Underwent randomization
99 Were assigned to the lopinavir–ritonavir
group and were included in the
intention-to-treat population
100 Were assigned to the standard care
group and were included in the
intention-to-treat population
3 Died within 24 hours after
admission and did not
receive lopinavir–ritonavir
100 Were included in the modified
intention-to-treat population
96 Were included in the modified
intention-to-treat population
2 Did not receive
lopinavir–ritonavir
1 Received lopinavir–ritonavir
on day 10
95 Were included in the safety population
99 Were included in the safety population
Figure 1. Randomization and Treatment Assignment.
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5
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Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*
Total
(N = 199)
Lopinavir–Ritonavir
(N = 99)
Standard Care
(N = 100)
58.0 (49.0–68.0)
58.0 (50.0–68.0)
58.0 (48.0–68.0)
120 (60.3)
61 (61.6)
59 (59.0)
Diabetes
23 (11.6)
10 (10.1)
13 (13.0)
Cerebrovascular disease
13 (6.5)
5 (5.1)
8 (8.0)
6 (3.0)
5 (5.1)
1 (1.0)
36.5 (36.4–36.8)
36.5 (36.4–37.0)
36.5 (36.5–36.8)
182 (91.5)
89 (89.9)
93 (93.0)
16 (16.0)
Characteristic
Age, median (IQR) — yr
Male sex — no. (%)
Coexisting conditions — no. (%)
Cancer
Body temperature, median (IQR) — °C
Fever — no. (%)
37 (18.8)
21 (21.6)
Systolic blood pressure 24/min — no. (%)
2 (1.0)
2 (2.0)
0
White-cell count (×10−9/liter) — median (IQR)
7.0 (5.1–9.4)
7.3 (5.3–9.6)
6.9 (4.9–9.1)
137 (70.3)
64 (67.4)
73 (73.0)
20 (10.3)
12 (12.6)
8 (8.0)
4–10 ×10−9/liter — no. (%)
133 μmol/liter — no. (%)
6 (3.1)
3 (3.1)
3 (3.0)
34.0 (26.0–45.0)
33.0 (25.0–42.0)
34.0 (27.0–45.0)
≤40 U/liter — no. (%)
155 (79.5)
78 (81.3)
77 (77.8)
>40 U/liter — no. (%)
40 (20.5)
18 (18.8)
22 (22.2)
33.0 (22.0–55.0)
33.0 (22.0–53.5)
34.0 (22.0–59.0)
115 (59.0)
61 (63.5)
54 (54.5)
50 U/liter — no. (%)
80 (41.0)
35 (36.5)
45 (45.5)
325.0 (245.0–433.0)
322.0 (243.0–409.0)
327.0 (245.0–470.0)
≤245 U/liter — no. (%)
50 (25.8)
24 (25.3)
26 (26.3)
>245 U/liter — no. (%)
144 (74.2)
71 (74.7)
73 (73.7)
Lactate dehydrogenase (U/liter) — median (IQR)
Creatine kinase (U/liter) — median (IQR)
69.0 (44.0–115.0)
57.0 (42.0–126.0)
72.0 (45.0–110.0)
≤185 U/liter — no. (%)
168 (86.6)
81 (85.3)
87 (87.9)
> 185 U/liter — no. (%)
26 (13.4)
14 (14.7)
12 (12.1)
* The values shown are based on available data. Laboratory values for white-cell count, lymphocyte count, platelet count, lactate dehydrogenase, and creatine kinase were available for 95 patients in the lopinavir–ritonavir group; and values for serum creatinine, aspartate aminotransferase, and alanine aminotransferase were available for 96 patients in that group. Laboratory values for serum creatinine, aspartate
aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase were available for 99 patients in the standard-care
group. To convert the values for creatinine to milligrams per deciliter, divide by 88.4. IQR denotes interquartile range.
6
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Trial of Lopinavir–Ritonavir in Severe Covid-19
Table 2. Patients’ Status and Treatments Received at or after Enrollment.*
Characteristic
NEWS2 score at day 1 — median (IQR)
Total
(N = 199)
Lopinavir–Ritonavir
(N = 99)
Standard Care
(N = 100)
5.0 (4.0–6.0)
5.0 (4.0–6.0)
5.0 (4.0–7.0)
Seven-category scale at day 1
3: Hospitalization, not requiring supplemental oxygen — no. (%)
28 (14.1)
11 (11.1)
17 (17.0)
4: Hospitalization, requiring supplemental oxygen — no. (%)
139 (69.8)
72 (72.7)
67 (67.0)
5: Hospitalization, requiring HFNC or noninvasive mechanical
ventilation — no. (%)
31 (15.6)
15 (15.2)
16 (16.0)
1 (0.5)
1 (1.0)
0
13 (11–16)
13 (11–17)
13 (10–16)
Earlier (≤12 days of symptom onset) — no. (%)
90 (45.2)
42 (42.4)
48 (48.0)
Later (>12 days of symptom onset) — no. (%)
109 (54.8)
57 (57.6)
52 (52.0)
Mean viral load — log10 copies per ml at day 1
4.0±2.1
4.4±2.0
3.7±2.1
Using interferon at enrollment — no. (%)
22 (11.1)
9 (9.1)
13 (13.0)
44 (22.1)
17 (17.2)
27 (27.0)
9 (4.5)
3 (3.0)
6 (6.0)
Noninvasive mechanical ventilation
29 (14.6)
10 (10.1)
19 (19.0)
Invasive mechanical ventilation
32 (16.1)
14 (14.1)
18 (18.0)
6: Hospitalization, requiring ECMO, invasive mechanical
ventilation, or both — no. (%)
Days from illness onset to randomization — median (IQR)
Treatments during study period — no. (%)
Vasopressors
Renal-replacement therapy
ECMO
Antibiotic agent
Glucocorticoid therapy
Days from illness onset to glucocorticoid therapy —
median (IQR)
Days of glucocorticoid therapy — median (IQR)
4 (2.0)
2 (2.0)
2 (2.0)
189 (95.0)
94 (94.9)
95 (95.0)
67 (33.7)
32 (32.3)
35 (35.0)
13 (11–17)
13 (12–19)
13 (9–17)
6 (3–11)
7 (3–11)
6 (2–12)
* Plus–minus values are means ±SD. ECMO denotes extracorporeal membrane oxygenation, HFNC high-flow nasal cannula for oxygen therapy, and NEWS2 National Early Warning Score 2.
28.8) (Fig. S5). There were no significant differences for other outcomes such as duration of
oxygen therapy, duration of hospitalization, and
time from randomization to death.
Virology
RNA loads over time did not differ between the
lopinavir–ritonavir recipients and those receiving
standard care (Fig. 3), including analysis according to duration of illness (Fig. S6).
The percentage of patients with detectable viral RNA for SARS-CoV-2 was similar in the lopinavir–ritonavir group and the standard-care group
on any sampling day (day 5, 34.5% vs. 32.9%; day
10, 50.0% vs. 48.6%; day 14, 55.2% vs. 57.1%;
day 21, 58.6% vs. 58.6%; and day 28, 60.3% vs.
58.6%) (Table S2).
A total of 69 patients (35%) who had a diagnostic respiratory tract sample that was positive on
RT-PCR had a negative RT-PCR result on the
throat swab taken after consent. The mean (±SD)
baseline viral RNA loads in the throat swabs
taken after consent were slightly higher in the
lopinavir–ritonavir group than in the standard- Safety
care group at randomization (4.4±2.0 log10 cop- A total of 46 patients (48.4%) in the lopinavir–
ies per milliliter vs. 3.7±2.1) (Table 2). The viral ritonavir group and 49 (49.5%) in the standard-
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7
The
n e w e ng l a n d j o u r na l
Cumulative Improvement Rate
1.0
0.9
Lopinavir–ritonavir
0.8
0.7
Control
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1
4
8
12
16
20
24
28
50
60
33
39
26
32
22
30
Day
No. at Risk
Lopinavir–ritonavir
Control
99
100
98
100
93
98
78
88
Figure 2. Time to Clinical Improvement in the Intention-to-Treat Population.
care group reported adverse events between randomization and day 28 (Table 4). Gastrointestinal
adverse events including nausea, vomiting, and
diarrhea were more common in lopinavir–ritonavir
group than in the standard-care group (Table 4).
The percentages of patients with laboratory abnormalities were similar in the two groups (Table 4). Serious adverse events occurred in 51 patients: 19 events in the lopinavir–ritonavir group
and 32 events in the standard-care group (Table 4). There were 4 serious gastrointestinal adverse events in the lopinavir–ritonavir group but
none in the standard-care group; all 4 events were
judged by the investigators to be related to the
trial medication. Respiratory failure, acute kidney
injury, and secondary infection were more common in patients receiving standard care. All deaths
during the observation period were judged by
the site investigators to be unrelated to the intervention.
Discussion
This randomized trial found that lopinavir–ritonavir treatment added to standard supportive care
was not associated with clinical improvement or
mortality in seriously ill patients with Covid-19
different from that associated with standard
care alone. However, in the modified intentionto-treat analysis, which excluded three patients
with early death, the between-group difference in
8
of
m e dic i n e
the median time to clinical improvement (median,
15 days vs. 16 days) was significant, albeit modest. Of note, the overall mortality in this trial
(22.1%) was substantially higher than the 11% to
14.5% mortality reported in initial descriptive
studies of hospitalized patients with Covid-19,1,2
which indicates that we enrolled a severely ill
population.
Our patient population was heterogeneous with
regard to duration and severity of illness at enrollment. In a post hoc subgroup analysis, the
difference in mortality between the lopinavir–
ritonavir group and the standard-care group was
observed to be numerically greater among patients treated within 12 days after the onset of
symptoms than among those treated later. The
question of whether earlier lopinavir–ritonavir
treatment in Covid-19 could have clinical benefit
is an important one that requires further study.
The finding is consistent with studies showing
that patients with SARS-CoV-2 viral pneumonia
have progression in the second week of illness1
and with the time-to-treatment effects observed
in previous antiviral studies in SARS20 and severe
influenza.21-23 In addition, we found that the numbers of lopinavir–ritonavir recipients who had serious complications (acute kidney injury and secondary infections) or requiring noninvasive or
invasive mechanical ventilation for respiratory
failure were fewer than in those not receiving
treatment. These observations are hypothesisgenerating and require additional studies to determine whether lopinavir–ritonavir treatment
given at a certain stage of illness can reduce some
complications in Covid-19.
We did not find that adding lopinavir–ritonavir treatment reduced viral RNA loads or duration
of viral RNA detectability as compared with standard supportive care alone. SARS-CoV-2 RNA was
still detected in 40.7% of the patients in the
lopinavir–ritonavir group at end of the trial (day
28). A recent report showed that the median
duration of viral shedding in Covid-19 was 20
days in patients with severe illness and could be
as long as 37 days.24 Neither that study nor the
current one found evidence that lopinavir–ritonavir exerted a significant antiviral effect. The
reasons for the apparent lack of antiviral effect
are uncertain, but the sampling methods used in
the current trial were most likely suboptimal.
Samples were taken only intermittently (on days
1, 5, 10, 14, 21, and 28), and more frequent sam-
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Trial of Lopinavir–Ritonavir in Severe Covid-19
Table 3. Outcomes in the Intention-to-Treat Population.*
Characteristic
Time to clinical improvement — median no.
of days (IQR)
Day 28 mortality — no. (%)
Earlier (≤12 days after onset of symptoms)
Later (>12 days after onset of symptoms)
Clinical improvement — no. (%)
Day 7
Day 14
Day 28
ICU length of stay — median no. of days
(IQR)
Of survivors
Of nonsurvivors
Duration of invasive mechanical ventilation —
median no. of days (IQR)
Oxygen support — days (IQR)
Hospital stay — median no. of days (IQR)
Time from randomization to discharge — median no. of days (IQR)
Time from randomization to death — median
no. of days (IQR)
Score on seven-category scale at day 7 — no.
of patients (%)
2: Not hospitalized, but unable to resume
normal activities
3: Hospitalization, not requiring supplemental oxygen
4: Hospitalization, requiring supplemental
oxygen
5: Hospitalization, requiring HFNC or
noninvasive mechanical ventilation
6: Hospitalization, requiring ECMO, invasive mechanical ventilation, or both
7: Death
Seven-category scale at day 14 — no. of patients (%)
2: Not hospitalized, but unable to resume
normal activities
3: Hospitalization, not requiring supplemental oxygen
4: Hospitalization, requiring supplemental
oxygen
5: Hospitalization, requiring HFNC or
noninvasive mechanical ventilation
6: Hospitalization, requiring ECMO, invasive mechanical ventilation, or both
7: Death
Total
(N = 199)
Lopinavir–Ritonavir
(N = 99)
Standard Care
(N = 100)
Difference†
16.0 (15.0 to 17.0)
16.0 (13.0 to 17.0)
16.0 (15.0 to 18.0)
1.31 (0.95 to 1.80)‡
44 (22.1)
21 (23.3)
23 (21.1)
19 (19.2)§
8 (19.0)
11 (19.3)
25 (25.0)
13 (27.1)
12 (23.1)
−5.8 (−17.3 to 5.7)
−8.0 (−25.3 to 9.3)
−3.8 (−19.1 to 11.6)
8 (4.0)
75 (37.7)
148 (74.4)
10 (5 to 14)
6 (6.1)
45 (45.5)
78 (78.8)
6 (2 to 11)
2 (2.0)
30 (30.0)
70 (70.0)
11 (7 to 17)
4.1 (−1.4 to 9.5)
15.5 (2.2 to 28.8)
8.8 (−3.3 to 20.9)
−5 (−9 to 0)
10 (8 to 17)
10 (4 to 14)
5 (3 to 9)
9 (5 to 44)
6 (2 to 11)
4 (3 to 7)
11 (9 to 14)
12 (7 to 17)
5 (3 to 9)
−1 (−16 to 38)
−6 (−11 to 0)
−1 (−4 to 2)
13 (8 to 16)
15 (12 to 17)
13 (10 to 16)
12 (9 to 16)
14 (12 to 17)
12 (10 to 16)
13 (6 to 16)
16 (13 to 18)
14 (11 to 16)
0 (−2 to 2)
1 (0 to 2)
1 (0 to 3)
10 (6 to 15)
9 (6 to 13)
12 (6 to 15)
−3 (−6 to 2)
4 (2.0)
4 (4.0)
0
29 (14.6)
12 (12.1)
17 (17.0)
109 (54.8)
58 (58.6)
51 (51.0)
35 (17.6)
14 (14.1)
21 (21.0)
10 (5.0)
6 (6.1)
4 (4.0)
12 (6.0)
5 (5.1)
7 (7.0)
71 (35.7)
43 (43.4)
28 (28.0)
32 (16.1)
8 (8.1)
24 (24.0)
45 (22.6)
25 (25.3)
20 (20.0)
11 (5.5)
5 (5.1)
6 (6.0)
8 (4.0)
3 (3.0)
5 (5.0)
32 (16.1)
15 (15.2)
17 (17.0)
* Clinical improvement was defined as a decline of two categories on the modified seven-category ordinal scale of clinical status, or hospital
discharge. ICU denotes intensive care unit.
† Differences were expressed as rate differences or median differences (Hodges–Lehmann estimate) and 95% confidence intervals.
‡ The hazard ratio for clinical improvement was estimated by Cox proportional-risk model.
§ This total includes 3 patients who died within 24 hours after randomization and did not receive lopinavir–ritonavir.
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9
The
n e w e ng l a n d j o u r na l
8
7
Viral Load
(log10 copies/ml)
6
5
4
3
2
Lopinavir–ritonavir
Control
1
0
1
5
10
14
21
28
Day
Figure 3. Mean Change from Baseline in SARS-CoV-2 Viral RNA Load
by qPCR on Throat Swabs.
I bars indicate 95% confidence intervals. Results less than the lower limit of
quantification of polymerase-chain-reaction (PCR) assay and greater than
the limit of qualitative detection are imputed with 1 log10 copies per milliliter; results for patients with viral-negative RNA are imputed with 0 log10
copies per milliliter. Among the 199 patients, 130 (59 patients in the lopinavir–ritonavir group and 71 in the standard-care group) had virologic data
that were used for viral load calculation, whereas the rest of the patients
had undetectable viral RNA on throat swabs over the time.
pling in the first 5 days could have provided
more detailed characterization of viral load kinetics in the two groups over this critical period.
In addition, previous studies have shown that
throat-swab specimens have lower viral loads
than nasopharyngeal samples,25 and importantly, we were unable to do sampling of lower respiratory tract secretions. Of note, depending on
cell type used, the 50% effective concentrations
(EC50) of lopinavir in vitro for SARS-CoV has
ranged from 4.0 to 10.7 μg per milliliter,5,6,8 although other studies reported that lopinavir was
inactive26 or that higher concentrations (25 μg
per milliliter) were required for inhibition.7 For
MERS-CoV, the EC50 values have ranged from 5 to
approximately 7 μg per milliliter).1,8,13 Both the
mean peak (9.6 μg per milliliter) and trough
(5.5 μg per milliliter) serum concentrations of
lopinavir in adults just approach these concentrations. Whether the EC50 value is an adequate
threshold and whether unbound lopinavir concentrations in human plasma are sufficient for
inhibition of SARS-CoV-2 are questionable.1
Nearly 14% of lopinavir–ritonavir recipients
10
of
m e dic i n e
were unable to complete the full 14-day course of
administration. This was due primarily to gastrointestinal adverse events, including anorexia,
nausea, abdominal discomfort, or diarrhea, as well
as two serious adverse events, both acute gastritis.
Two recipients had self-limited skin eruptions.
Such side effects, including the risks of hepatic
injury, pancreatitis, more severe cutaneous eruptions, and QT prolongation, and the potential
for multiple drug interactions due to CYP3A inhibition, are well documented with this drug combination. The side-effect profile observed in the
current trial arouses concern about the use of
higher or more prolonged lopinavir–ritonavir
dose regimens in efforts to improve outcomes.
Our trial has several limitations. In particular, the trial was not blinded, so it is possible
that knowledge of the treatment assignment
might have influenced clinical decision-making
that could have affected the ordinal scale measurements we used. We will continue to follow
these patients to evaluate their long-term prognosis. The characteristics of the patients at baseline were generally balanced across the two groups,
but the somewhat higher throat viral loads in the
lopinavir–ritonavir group raise the possibility
that this group had more viral replication. Although we did not observe differences between
groups in the frequency of use of concurrent pharmacologic interventions, such as glucocorticoids,
this might have been another confounder. In addition, approximately 45% and 40% of the patients in lopinavir–ritonavir group had positive
RNA detection by throat swabs on day 14 and day
28, respectively, but we do not know if infectious
virus was still present, since we did not attempt
virus isolation or assess the possible emergence
of SARS-CoV-2 variants with reduced susceptibility to lopinavir. Finally, we do not have data
on the lopinavir exposure levels in these seriously and often critically ill patients.
In conclusion, we found that lopinavir–ritonavir treatment did not significantly accelerate
clinical improvement, reduce mortality, or diminish throat viral RNA detectability in patients with
serious Covid-19. These early data should inform
future studies to assess this and other medication
in the treatment of infection with SARS-CoV-2.
Whether combining lopinavir–ritonavir with other antiviral agents, as has been done in SARS5,20
and is being studied in MERS-CoV,15 might en-
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Trial of Lopinavir–Ritonavir in Severe Covid-19
Table 4. Summary of Adverse Events in the Safety Population.*
Event
Lopinavir–Ritonavir (N = 95)
Any Grade
Grade 3 or 4
Standard Care (N = 99)
Any Grade
Grade 3 or 4
number (percent)
Any adverse event
46 (48.4)
20 (21.1)
49 (49.5)
11 (11.1)
Lymphopenia
16 (16.8)
12 (12.6)
12 (12.1)
5 (5.1)
Nausea
9 (9.5)
1 (1.1)
0
0
Thrombocytopenia
6 (6.3)
1 (1.1)
10 (10.1)
2 (2.0)
Leukopenia
7 (7.4)
1 (1.1)
13 (13.1)
0
Vomiting
6 (6.3)
0
0
0
Increased aspartate aminotransferase
2 (2.1)
2 (2.1)
5 (5.1)
4 (4.0)
Abdominal discomfort
4 (4.2)
0
2 (2.1)
0
Diarrhea
4 (4.2)
0
0
0
Stomach ache
4 (4.2)
1 (1.1)
1 (1.0)
0
Neutropenia
4 (4.2)
1 (1.1)
8 (7.6)
0
Increased total bilirubin
3 (3.2)
3 (3.2)
3 (3.0)
2 (2.0)
Increased creatinine
2 (2.1)
2 (2.1)
7 (7.1)
6 (6.1)
Anemia
2 (2.1)
2 (2.1)
5 (5.0)
4 (4.0)
Rash
2 (2.1)
0
0
0
Hypoalbuminemia
1 (1.1)
1 (1.1)
4 (4.0)
1 (1.0)
Increased alanine aminotransferase
1 (1.1)
1 (1.1)
4 (4.0)
1 (1.0)
0
0
1 (1.0)
0
Increased creatine kinase
Decreased appetite
2 (2.1)
0
0
0
Prolonged QT interval
1 (1.1)
0
0
0
Sleep disorders and disturbances
1 (1.1)
0
0
0
Facial flushing
1 (1.1)
0
0
0
Serious adverse event
19 (20.0)
17 (17.9)
32 (32.3)
31 (31.3)
12 (12.6)
12 (12.6)
27 (27.3)
27 (27.3)
Acute kidney injury
3 (3.2)
2 (2.1)
6 (6.1)
5 (5.1)
Secondary infection
1 (1.1)
1 (1.1)
6 (6.1)
6 (6.1)
Shock
2 (2.1)
2 (2.1)
2 (2.0)
2 (2.0)
Severe anemia
3 (3.2)
3 (3.2)
0
0
Acute gastritis
2 (2.1)
0
0
0
Hemorrhage of lower digestive tract
2 (2.1)
1 (1.1)
0
0
2 (2.0)
Respiratory failure or ARDS
0
0
2 (2.0)
Unconsciousness
Pneumothorax
1 (1.1)
0
0
0
Disseminated intravascular coagulation
1 (1.1)
0
1 (1.0)
1 (1.0)
Sepsis
0
0
1 (1.0)
1 (1.0)
Acute heart failure
0
0
1 (1.0)
1 (1.0)
* Adverse events that occurred in more than 1 patient after randomization through day 28 are shown. Some patients
had more than one adverse event. Since there are no adverse event grades criteria for serum levels of hypersensitivity
troponin (cardiac biomarker) and serum lipid, the proportions of patients with values worse than baseline values are
listed here. The proportion of increased hypersensitivity troponin was higher in the standard-care group than in the
lopinavir–ritonavir group (14.1% vs. 9.5%). A total of 55 patients (52.4%) in the standard-care group and 65 (68.4%) in
the lopinavir–ritonavir group had lipid levels that were normal at enrollment but abnormal after enrollment. All deaths
were due to respiratory failure. ARDS indicates acute respiratory distress syndrome.
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11
The
n e w e ng l a n d j o u r na l
hance antiviral effects and improve clinical outcomes remains to be determined.
Supported by grants from Major Projects of National Science and Technology on New Drug Creation and Development
(2020ZX09201001) and (2020ZX09201012); the Chinese Academy of Medical Sciences (CAMS) Emergency Project of Covid-19
(2020HY320001); and a National Science Grant for Distinguished
Young Scholars (81425001/H0104). Dr. Jaki is a recipient of a
National Institute for Health Research Senior Research Fellowship (2015-08-001). Dr. Horby reports receiving funding from the
Wellcome Trust, the Bill and Melinda Gates Foundation, and the
United Kingdom Department of Health and Social Care.
of
m e dic i n e
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank all patients who participated in this trial and their
families. We also thank Bandar Al Knawy and Yaseen Arabi
for sharing the MIRACLE trial documentation and meeting
reports from WHO Novel Coronavirus R&D. Teddy Clinical
Research Laboratory (Shanghai) served as the central laboratory, and Roche Diagnostics (Shanghai) provided instruments
and SARS-CoV-2 assay detection. We dedicate this work to the
memory of health care workers who have given their lives in
the care of patients with Covid-19.
Appendix
The authors’ full names and academic degrees are as follows: Bin Cao, M.D., Yeming Wang, M.D., Danning Wen, M.D., Wen Liu, M.S.,
Jingli Wang, M.D., Guohui Fan, M.S., Lianguo Ruan, M.D., Bin Song, M.D., Yanping Cai, M.D., Ming Wei, M.D., Xingwang Li, M.D.,
Jiaan Xia, M.D., Nanshan Chen, M.D., Jie Xiang, M.D., Ting Yu, M.D., Tao Bai, M.D., Xuelei Xie, M.D., Li Zhang, M.D., Caihong Li,
M.D., Ye Yuan, M.D., Hua Chen, M.D., Huadong Li, M.D., Hanping Huang, M.D., Shengjing Tu, M.D., Fengyun Gong, M.D., Ying Liu,
M.S., Yuan Wei, M.D., Chongya Dong, Ph.D., Fei Zhou, M.D., Xiaoying Gu, Ph.D., Jiuyang Xu, M.D., Zhibo Liu, M.D., Yi Zhang, M.D.,
Hui Li, M.D., Lianhan Shang, M.D., Ke Wang, M.D., Kunxia Li, M.D., Xia Zhou, M.D., Xuan Dong, M.D., Zhaohui Qu, M.D., Sixia Lu,
M.D., Xujuan Hu, M.D., Shunan Ruan, M.S., Shanshan Luo, M.D., Jing Wu, M.D., Lu Peng, M.D., Fang Cheng, M.D., Lihong Pan, M.D.,
Jun Zou, M.D., Chunmin Jia, M.D., Juan Wang, M.D., Xia Liu, M.D., Shuzhen Wang, M.S., Xudong Wu, M.S., Qin Ge, M.S., Jing He,
M.S., Haiyan Zhan, M.S., Fang Qiu, M.S., Li Guo, Ph.D., Chaolin Huang, M.D., Thomas Jaki, Ph.D., Frederick G. Hayden, M.D., Peter W. Horby, M.D., Dingyu Zhang, M.D., and Chen Wang, M.D.
The authors’ affiliations are as follows: the Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine,
National Clinical Research Center for Respiratory Diseases (B.C., Yeming Wang, G.F., F.Z., X.G., Z.L., Y.Z., Hui Li, L.S., C.W.), and the
Institute of Clinical Medical Sciences (G.F., X.G.), China–Japan Friendship Hospital, the Institute of Respiratory Medicine, Chinese
Academy of Medical Sciences (B.C., Yeming Wang, F.Z., Z.L., Y.Z., Hui Li, C.W.), the Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University (Xingwang Li), Peking University Clinical Research Institute, Peking University First Hospital (C.D.), Tsinghua University School of Medicine (Jiuyang Xu), Beijing University of Chinese Medicine (L.S.), NHC Key
Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of
Medical Sciences (L.G.), and Peking Union Medical College (L.G., C.W.), Beijing, and Jin Yin-tan Hospital, Wuhan (D.W., W.L., Jingli
Wang, L.R., B.S., Y.C., M.W., Jiaan Xia, N.C., Jie Xiang, T.Y., T.B., X.X., L.Z., C.L., Y.Y., H.C., Huadong Li, H.H., S.T., F.G., Y.L., Yuan
Wei, K.W., K.L., X.Z., X.D., Z.Q., Sixia Lu, X.H., S.R., Shanshan Luo, Jing Wu, Lu Peng, F.C., Lihong Pan, J.Z., C.J., Juan Wang, Xia
Liu, S.W., X.W., Q.G., J.H., H.Z., F.Q., C.H., D.Z.) — all in China; Lancaster University, Lancaster (T.J.), and the University of Oxford,
Oxford (P.W.H.) — both in the United Kingdom; and the University of Virginia School of Medicine, Charlottesville (F.G.H.).
References
1. Huang C, Wang Y, Li X, et al. Clinical
features of patients infected with 2019
novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
2. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of
99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive
study. Lancet 2020;395:507-13.
3. Wang D, Hu B, Hu C, et al. Clinical
characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA
2020 February 7 (Epub ahead of print).
4. Liu K, Fang YY, Deng Y, et al. Clinical
characteristics of novel coronavirus cases
in tertiary hospitals in Hubei Province.
Chin Med J (Engl) 2020 February 7 (Epub
ahead of print).
5. Chu CM, Cheng VC, Hung IF, et al.
Role of lopinavir/ritonavir in the treatment
of SARS: initial virological and clinical
findings. Thorax 2004;59:252-6.
6. Chen F, Chan KH, Jiang Y, et al. In
vitro susceptibility of 10 clinical isolates
of SARS coronavirus to selected antiviral
compounds. J Clin Virol 2004;31:69-75.
12
Wu C-Y, Jan J-T, Ma S-H, et al. Small
molecules targeting severe acute respiratory syndrome human coronavirus. Proc
Natl Acad Sci U S A 2004;101:10012-7.
8. de Wilde AH, Jochmans D, Posthuma
CC, et al. Screening of an FDA-approved
compound library identifies four smallmolecule inhibitors of Middle East respiratory syndrome coronavirus replication
in cell culture. Antimicrob Agents Chemother 2014;58:4875-84.
9. Chan JF-W, Yao Y, Yeung M-L, et al.
Treatment with lopinavir/ritonavir or
interferon-β1b improves outcome of
MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis 2015;212:1904-13.
10. Kim UJ, Won E-J, Kee S-J, Jung S-I,
Jang H-C. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-α
for Middle East respiratory syndrome.
Antivir Ther 2016;21:455-9.
11. Spanakis N, Tsiodras S, Haagmans
BL, et al. Virological and serological
analysis of a recent Middle East respiratory syndrome coronavirus infection
case on a triple combination antiviral
7.
regimen. Int J Antimicrob Agents 2014;
44:528-32.
12. Min C-K, Cheon S, Ha N-Y, et al. Comparative and kinetic analysis of viral shedding and immunological responses in
MERS patients representing a broad spectrum of disease severity. Sci Rep 2016;6:
25359.
13. Chan JFW, Chan K-H, Kao RYT, et al.
Broad-spectrum antivirals for the emerging Middle East respiratory syndrome
coronavirus. J Infect 2013;67:606-16.
14. Hart BJ, Dyall J, Postnikova E, et al.
Interferon-β and mycophenolic acid are
potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based
assays. J Gen Virol 2014;95:571-7.
15. Arabi YM, Alothman A, Balkhy HH, et
al. Treatment of Middle East Respiratory
Syndrome with a combination of lopinavirritonavir and interferon-β1b (MIRACLE
trial): study protocol for a randomized
controlled trial. Trials 2018;19:81.
16. International Severe Acute Respiratory and Emerging Infections Consortium
(ISARIC) home page (https://isaric
.tghn
.org/).
n engl j med nejm.org
The New England Journal of Medicine
Downloaded from nejm.org on March 24, 2020. For personal use only. No other uses without permission.
Copyright © 2020 Massachusetts Medical Society. All rights reserved.
Trial of Lopinavir–Ritonavir in Severe Covid-19
17. Wang Y, Fan G, Salam A, et al. Com-
parative effectiveness of combined favipiravir and oseltamivir therapy versus oseltamivir monotherapy in critically ill
patients with influenza virus infection.
J Infect Dis 2019 December 11 (Epub
ahead of print).
18. Coronavirus disease (COVID-2019)
R&D. Geneva:World Health Organization
(http://www.who.int/blueprint/priority
-d iseases/key-action/novel-coronavirus/
en/).
19. National Early Warning Score (NEWS)
2:standardising the assessment of acuteillness severity in the NHS. London:Royal
College of Physicians, 2017 (https://www
.rcplondon.ac.uk/projects/outputs/national
-early-warning-score-news-2).
20. Chan KS, Lai ST, Chu CM, et al. Treat-
ment of severe acute respiratory syndrome
with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong
Kong Med J 2003;9:399-406.
21. Muthuri SG, Venkatesan S, Myles PR,
et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients
admitted to hospital with influenza A
H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet
Respir Med 2014;2:395-404.
22. Louie JK, Yang S, Acosta M, et al.
Treatment with neuraminidase inhibitors
for critically ill patients with influenza A
(H1N1)pdm09. Clin Infect Dis 2012;
55:
1198-204.
23. Katzen J, Kohn R, Houk JL, Ison MG.
Early oseltamivir after hospital admission
is associated with shortened hospitaliza-
tion: a 5-year analysis of oseltamivir timing and clinical outcomes. Clin Infect Dis
2019;69:52-8.
24. Zhou F, Yu T, Du R, et al. Clinical
course and risk factors for mortality of
adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
Lancet 2020 March 11 (Epub ahead of
print).
25. Zou L, Ruan F, Huang M, et al. SARSCoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med.
DOI: 10.1056/NEJMc2001737.
26. Yamamoto N, Yang R, Yoshinaka Y, et
al. HIV protease inhibitor nelfinavir inhibits replication of SARS-associated
coronavirus. Biochem Biophys Res Commun 2004;318:719-25.
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13
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Original Article
A Randomized Trial of E-Cigarettes
versus Nicotine-Replacement Therapy
Peter Hajek, Ph.D., Anna Phillips‑Waller, B.Sc., Dunja Przulj, Ph.D.,
Francesca Pesola, Ph.D., Katie Myers Smith, D.Psych., Natalie Bisal, M.Sc.,
Jinshuo Li, M.Phil., Steve Parrott, M.Sc., Peter Sasieni, Ph.D.,
Lynne Dawkins, Ph.D., Louise Ross, Maciej Goniewicz, Ph.D., Pharm.D.,
Qi Wu, M.Sc., and Hayden J. McRobbie, Ph.D.
A BS T R AC T
BACKGROUND
E-cigarettes are commonly used in attempts to stop smoking, but evidence is limited
regarding their effectiveness as compared with that of nicotine products approved as
smoking-cessation treatments.
METHODS
We randomly assigned adults attending U.K. National Health Service stop-smoking
services to either nicotine-replacement products of their choice, including product
combinations, provided for up to 3 months, or an e-cigarette starter pack (a secondgeneration refillable e-cigarette with one bottle of nicotine e-liquid [18 mg per milliliter]), with a recommendation to purchase further e-liquids of the flavor and strength
of their choice. Treatment included weekly behavioral support for at least 4 weeks. The
primary outcome was sustained abstinence for 1 year, which was validated biochemically at the final visit. Participants who were lost to follow-up or did not provide biochemical validation were considered to not be abstinent. Secondary outcomes included
participant-reported treatment usage and respiratory symptoms.
From Queen Mary University of London
(P.H., A.P.-W., D.P., K.M.S., N.B., H.J.M.),
King’s College London (F.P., P.S.), and
London South Bank University (L.D.),
London, the University of York, York (J.L.,
S.P., Q.W.), and Leicester City Council,
Leicester (L.R.) — all in the United Kingdom; and Roswell Park Comprehensive
Cancer Center, Buffalo, NY (M.G.). Address reprint requests to Dr. Przulj at
Queen Mary University of London, Health
and Lifestyle Research Unit, 2 Stayner’s
Rd., London E1 4AH, United Kingdom, or
at d.przulj@qmul.ac.uk.
This article was published on January 30,
2019, at NEJM.org.
N Engl J Med 2019;380:629-37.
DOI: 10.1056/NEJMoa1808779
Copyright © 2019 Massachusetts Medical Society.
RESULTS
A total of 886 participants underwent randomization. The 1-year abstinence rate was
18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement
group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P