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A Trial of Lopinavir-Ritonavir in Adults
Hospitalized with Severe Covid-19
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March 18, 2020
https://www.nejm.org/doi/full/10.1056/NEJMoa2001282?query=featured_home
Abstract
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.
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. opens in new tab.)
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In the intention-to-treat population, lopinavir-ritonavir treatment within 12 days after the onset of symptoms was associated with shorter time to clinical improvement (hazard ratio, 1.25; 95% CI, 1.77 to 2.05), but later treatment with lopinavir-ritonavir was not (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).
Secondary Outcomes
The 28-day mortality was numerically lower in the lopinavir-ritonavir group than in the standard-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 higher in the lopinavir-ritonavir group than in the standard-care group (45.5% vs. 30.0%; difference, 15.5 percentage points; 95% CI, 2.2 to 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.
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Results
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 (Figure 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) (Figure 2). In the modified intention-to-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 associated with shorter time to clinical improvement (hazard ratio, 1.25; 95% CI, 1.77 to 2.05), but later treatment with lopinavir-ritonavir was not (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).
Secondary Outcomes
The 28-day mortality was numerically lower in the lopinavir-ritonavir group than in the standard-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 higher in the lopinavir-ritonavir group than in the standard-care group (45.5% vs. 30.0%; difference, 15.5 percentage points; 95% CI, 2.2 to 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
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-care group at randomization (4.4±2.0 log10 copies per milliliter vs. 3.7±2.1) (Table 2). The viral RNA loads over time did not differ between the lopinavir-ritonavir recipients and those receiving standard care (Figure 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).
Safety
A total of 46 patients (48.4%) in the lopinavir-ritonavir group and 49 (49.5%) in the standard-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.
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 intention-to-treat analysis, which excluded three patients with early death, the between-group difference in 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; accelerated clinical recovery (16.0 days vs. 17.0 days) and reduced mortality (19.0% vs. 27.1%) were observed in a post hoc subgroup of those treated within 12 days after the onset of symptoms, but not in those treated later (Fig. S2A and S2B). 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 hypothesis-generating 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 sampling 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 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 enhance antiviral effects and improve clinical outcomes remains to be determined.
Beginning 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 half-life 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. opens in new tab).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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