Cao et al, 2020 – “LOTUS China” trial of Lopinavir–Ritonavir for Covid-19 | INTENSIVE Review

Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 [published online ahead of print, 2020 Mar 18]. N Engl J Med. 2020;10.1056/NEJMoa2001282.

In this open label trial, authors from Jin Yin-Tan hospital near the epicentre of the SARS-CoV-2 outbreak have reported the first randomised controlled trial of the anti-retroviral agent lopinavir-ritonavir (Kaletra) in patients with COVID-19, which has previously shown in-vitro activity against the related SARS virus and has been reported in case-series for COVID-19.

Patients with PCR confirmed SARS-CoV-2 infection, plus radiographic evidence of pneumonia and oxygen saturations of ≤ 94% on ambient air or P/F ratio <300 mmHg were randomised to either lopinavir-ritonavir 400/100mg twice daily for 14 days, in addition to standard care, or standard care alone. The primary outcome was median time to clinical improvement of 2 points on a seven-point ordinal scale (ranges from home, to hospitalised with or without NIV or invasive supports to death) or alive at the time of discharge from the hospital, whichever occurred first.

199 patients were randomised prior to the trial being terminated due to the availability of an alternative study agent (remdesivir) which has also shown promising in-vitro activity.

The study found no significant differences in median time to clinical improvement (16 vs. 16 days, HR 1.31, 95% CI 0.95-1.85, p=0.09) or 28 day mortality. There was a significant reduction in ICU length of stay of -1 day and hospital length of stay of -1 day in survivors. When patients were stratified to early (≤12 days post symptom onset) vs. late (>12 days) lopinavir-ritonavir was associated with a statistically shorter time to clinical improvement (HR 1.25, 95% CI 1.77 to 2.05, median not reported). There were more serious adverse events in the standard group (32.3% vs 20%). However, 14% of patients in the intervention group could not complete their 14-day course mainly due to gastrointestinal side effects.  

This is the first randomised controlled trial of antiviral therapy for COVID-19 and has a clinically relevant outcome. Unlike remdesivir, lopinavir-ritonavir is an established therapy in HIV and is likely to be widely available.

Limitations of the study include that it was unblinded creating the potential for bias. The study did not measure the levels of lopinavir in the blood as absorption of oral/NG medication in patients who are acutely ill may be different.

This study also suggests benefit (if present) may be greatest for patients who are treated early in disease, thus the relevance for ICU clinicians is less certain. Only 16 patients were requiring high flow nasal prongs, NIV, invasive mechanical ventilation or ECMO on day 1 of the study.

At this stage, lopinavir-ritonavir remains experimental.   At a time when resources are overwhelmed, even small improvements in time to discharge from ICU and hospital may have great implications for hospital resource availability and patient throughput. Therefore larger trials are needed to confirm whether lopinavir-ritonavir is indeed associated with shorter hospital and/or ICU lengths of stay.

Futher reading:

• Chu CM, Cheng VCC, Hung IFN et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59:252-6. doi: 10.1136/thorax.2003.012658
• Sheahan T, Sims A, Leist S et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV Nature Communications 2020; 11:222, DOI: https://doi.org/10.1038/s41467-019-13940-6
• Young EB, Ong SWX, Kalimuddin S et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA; 2020 March 3. doi: 10.1001/jama.2020.3204

Tabulated summary

Category	Therapeutics
Study question	Does Lopinavir-Ritonavir (Kaletra), compared with placebo, result in improved clinical state on a seven point ordinal scale (below)?
Background	COVID-19 (COronaVIrus Disease 2019) is a viral respiratory syndrome caused by a novel coronavirus, SARS-CoV-2.   Lopinavir-Ritonavir (brand name Kaletra) is a combination anti-retroviral agent used in the treatment of Human Immunodeficiency Virus (HIV). Following the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome coronavirus (MERS-CoV) epidemics, Lopinavir-Ritonavir was identified as having in-vitro activity against these related coronaviruses [1], while human clinical trials are ongoing. Use of Lopinavir-Ritonavir in patients with COVID-19 has been reported in case series [2]   This is the first RCT to be reported using Lopinavir-Ritonavir in patients with COVID-19.
Design	Randomised, open label controlled trial.
Population	199 patients from Jin Yin-Tan hospital, Wuhan, China   Inclusion: Patients SARS-CoV-2 infection based on PCR sample from the respiratory tractFeatures of pneumonia on chest imagingSpO2 ≤ 94% on room air or PaO2:FiO2 ratio of < 300mmHgAged over 18 Exclusion: Pregnancy or breast feedingHIV infectionKnown allergy/hypersensitivity to Lopinavir-RitonavirSevere livery diseaseMedications that are known to interact with study drugPhysician discretion
Intervention	Lopinavir-ritonavir 400mg/100mg orally twice daily plus standard care 14 days
Control	Standard care for 14 days Randomisation by online, stratified, permuted blocks
Outcome(s)	Primary: Median time to improvement of two points on a seven-point ordinal scale: 1-2: not hospitalised, with vs. without resumption of normal activity3-4: hospitalised, room air vs. supplemental oxygen5: hospitalised, requiring high flow nasal oxygen or non-invasive ventilation6: hospitalised with invasive mechanical ventilation or ECMO7: death Or alive at the time of discharge, whichever occurred first. Secondary: 28 day mortality, duration of mechanical ventilation, hospital  length of stay, duration of viral PCR positivity   Sample size was chosen for an 80% power to detect an 8-day median difference in time to clinical improvement, assuming baseline of 20 days to 2-point clinical improvement in standard care group.   Initial sample size of 160 patients was extended due to insufficient power (median difference in time to clinical improvement of 8 days used for sample calculation was probably not realistic), before the trial was suspended due to an alternative clinical agent (remdesivir).
Key findings	199 patients with a median age of 58 years and a median duration between symptom onset and randomisation of 13 days.   Median time to clinical improvement of 2 points was not significantly different between groups 16 vs. 16 days, HR for improvement 1.31 (95% CI 0.95-1.85, p=0.09)   When patients were stratified to early (≤12 days post symptom onset) vs. late (>12 days) lopinavir-ritonavir was associated with a statistically shorter time to clinical improvement (HR 1.25, 95% CI 1.77 to 2.05, median times not reported).   28 day mortality was not significantly different (19% v.s. 25%, 95% CI -17.3 to 5.7%).   ICU length of stay shorter by 1 day days in treatment group (95% CI -9 to 0 days) and hospital length of stay shorter by 1 day (95% CI -3 to 0 days) for survivors.   There was no difference in viral shedding between groups and no difference the rate of adverse events.
Author’s conclusion:	“The addition of lopinavir-ritonavir to standard care was not associated with clinical improvement in seriously ill patients with COVID-19.”
Strengths	First randomised controlled trial of antiviral therapy in COVID-19   Clinically relevant primary outcome, which relates to both patient function as well as intensity of hospital resource utilisation (e.g. home vs. hospital, non-invasive vs. invasive supports).   Illness severity similar to other reported cohorts from Wuhan region [3-4].
Weaknesses	Underpowered for both primary and secondary end-points An 8-day difference in time to improvement was used for power calculationTrial extended, then terminated early due to alternative therapy becoming available, without establishing futility.   Open label – risk of bias in other “standard” care provided.   Three patients in treatment group died within 24 hours of randomisation and prior to treatment with lopinavir-ritonavir; in a modified intention to treat analysis these patients were excluded from the group, but no similar adjustment performed in control group (introduces bias into the adjusted end-point).   Uncertain relevance to ICU cohort – only 16% of patients were on high flow oxygen or mechanical ventilation at time of randomisation. Shorter ICU length of stay without corresponding differences in clinical improvement or hospital length of stay is unexplained Viral shedding no difference between the two groups. However, virus isolation was not attempted. Therefore, unclear whether they were live viruses.   The serum lopinavir levels were not measured as pharmacokinetics and pharmacodynamics of the oral/NG lopinavir may be altered in acutely ill patients. Single-centre study at the epicentre of SARS-CoV-2 outbreak means uncertain external validity for other settings.
Summary	In a (mostly) pre-ICU cohort of patients with COVID-19, lopinavir-ritonavir was not associated with reduced time to clinical improvement.   At this stage, lopinavir-ritonavir remains experimental.   At a time when resources are overwhelmed, even small improvements in time to discharge from ICU and hospital may have great implications for hospital resource availability and patient throughput. Therefore larger trials are needed to confirm whether lopinavir-ritonavir is indeed associated with shorter hospital and/or ICU lengths of stay.

[1] Chu CM, Cheng VCC, Hung IFN et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59:252-6. doi: 10.1136/thorax.2003.012658

[2] Young EB, Ong SWX, Kalimuddin S et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA; 2020 March 3. doi: 10.1001/jama.2020.3204

[3] Wang D, Hu B, Chang H et al. linical Characteristics of 138 Hospitalized Patients

With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020 February 7. doi:10.1001/jama.2020.1585

[4] 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 9. doi: 10.1016/S0140-6736(20)30566-3