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Cao B, et al. "A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19". The New England Journal of Medicine. 2020. 382(70):1787-1799.
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Clinical Question

In hospitalized patients with COVID-19 infection and hypoxia (SaO2 <94% on room air or PaO2:FiO2 <300 mm Hg), does the combination of lopinavir and ritonavir in addition to standard of care decrease the time to clinical improvement?

Bottom Line

Lopinavir-ritonavir does not decrease time to clinical improvement and does not reduce mortality in severe COVID-19 infection when compared to standard of care.

Major Points

At the time of the LOTUS China study, published in March of 2020, there were no proven treatments for COVID-19, and many antiviral agents were investigated. Lopinavir was known to have some in vitro and in vivo activity against SARS-CoV and MERS-CoV,[1][2] it is combined with ritonavir for increased half-life. A 2004 open-label study suggested some benefits in treating SARS.[3] LOTUS China showed no change between the standard of care with and without lopinavir-ritonavir in time to clinical improvement/hospital discharge or mortality.



  • Single-center, open-label, individually randomized, controlled trial
  • N=199
    • Lopinavir-ritonavir and standard of care (n=99)
    • Standard (n=100)
  • Setting: Jin Yin-Tan Hospital, Wuhan, Hubei Province, China
  • Enrollment: January 18, 2020 - February 3, 2020
  • Mean follow-up: 28 days
  • Analysis: Intention-to-treat
  • Primary outcome: Time to clinical improvement
  • Secondary outcomes:
    • Mortality at 28 days
    • Detectable viral RNA


Inclusion Criteria

  • Adult, non-pregnant patients
  • RT-PCR positive for SARS-CoV-2
  • Pneumonia on imaging
  • SaO2 <94% on room air OR
  • PaO2:FiO2 <300 mmHg

Exclusion Criteria

  • Allergy/hypersensitivity to either lopinavir or ritonavir
  • Severe liver disease (cirrhosis with AST or ALT >5x ULN)
  • Contraindicated medication interactions
  • Breastfeeding
  • Known HIV infection

Baseline Characteristics

  • Median age: 58.0 years
  • Median NEWS2 score day 1: 5.0
  • Mean viral load at day 1 (log10 copies/mL): 4.0


Patients were randomized to lopinavir-ritonavir (400 mg/100 mg) plus standard care or standard care alone


Comparisons are lopinavir-ritonavir with the standard of care vs. standard care alone.

Primary Outcomes

Time to clinical improvement or discharge from hospital
2.11% vs. 2.29% (HR 0.90; 95% CI 0.78-1.04; P=0.16)

Secondary Outcomes

Subgroup Analysis

Adverse Events

"Selected adverse events are shown below; refer to the article for a complete list."

Any adverse events
48.4% vs. 49.5%
Serious adverse event
20.0% vs. 32.3%
Respiratory failure or ARDS
12.6% vs. 27.3%
16.8% vs. 12.1%


  • The trial population was not blinded, which could influence the clinical decisions that were made and affect the utilized measurements.
  • The frequency of glucocorticoid use between the groups was not observed in the trial.


  • Funded by Major Projects of National Science and Technology on New Drug Creation and Development
  • All authors reported any disclosures or conflicts of interest; see ICMJE Form for Disclosure of Potential Conflicts of Interest for the full listing

Further Reading

  1. de Wilde AH et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014. 58:4875-84.
  2. Chan JF 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.
  3. Chu CM et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004. 59:252-6.