Lopinavir/Ritonavir: Selected Clinical Data
Last Updated: July 17, 2020
The information presented in this section may include data from preprints or articles that have not been peer reviewed. This section will be updated as new information becomes available. Please see ClinicalTrials.gov for more information on clinical trials that are evaluating lopinavir/ritonavir.
Randomized Controlled Trial of Lopinavir/Ritonavir Versus Standard of Care
In a clinical trial that randomized 199 patients to receive lopinavir 400 mg/ritonavir 100 mg orally twice daily for 14 days or standard of care, patients who were randomized to the lopinavir/ritonavir arm did not have a shorter time to clinical improvement.1
- There was a lower, but not statistically significant, mortality rate for the lopinavir/ritonavir group (19.2%) than for the standard of care group (25.0%), and a shorter median intensive care unit stay for those in the lopinavir/ritonavir group than for those in the standard of care group (6 days vs. 11 days; 95% CI, -9 to 0 days).
- There was no difference in the median duration of hospital stay and the median time to clearance of viral RNA from respiratory tract samples between the two arms.
- Nausea, vomiting, and diarrhea were all more frequent among patients in the lopinavir/ritonavir-treated group.
- The study was not blinded, which may have affected the assessments of clinical improvement.
- The study was underpowered to show small effects.
A moderately sized, randomized trial failed to find a virologic or clinical benefit of lopinavir/ritonavir over standard of care.
Lopinavir/Ritonavir Plus Interferon Beta-1b Plus Ribavirin in Patients with COVID-19
Also see Interferons for a description of this trial and its results.
An open-label, Phase 2 clinical trial randomized 127 participants with COVID-19 2:1 to receive either a 14-day course of a combination therapy that included interferon beta-1b 8 million international units administered subcutaneously on alternating days (1–3 doses, depending on time from symptom onset) plus lopinavir 400 mg/ritonavir 100 mg orally every 12 hours and ribavirin 400 mg orally every 12 hours, or a 14-day course of lopinavir/ritonavir 400 mg/100 mg every 12 hours alone.2
In the combination therapy group, those who were admitted <7 days after symptom onset (n = 52) received triple-drug therapy; however, interferon beta-1b was not included in the regimen for those who were admitted ≥7 days after symptom onset (n = 34) because of concerns regarding its potential for inflammatory effects. The study population consisted of patients who were hospitalized in Hong Kong; the median age was 52 years and the median time from symptom onset to enrollment was 5 days. Only 12% to 14% of participants were on supplemental oxygen, and only one participant was mechanically ventilated.
Patients in the combination therapy group showed faster viral clearance and more rapid clinical improvement than those in the control group.
- Participants in both arms received lopinavir/ritonavir, so it is impossible to determine whether lopinavir/ritonavir contributed to the observed treatment effects. However, the possibility that lopinavir/ritonavir may have contributed to the effectiveness of the combination therapy also cannot be ruled out.
- The positive clinical impact of the combination therapy was limited to those who were hospitalized <7 days from symptom onset.
- Most participants in this study had mild illness, and only slightly more than 10% were on supplemental oxygen. For this reason, the study has limited applicability to hospitalized patients in the United States.
This study neither supports nor refutes the use of lopinavir/ritonavir with or without ribavirin in patients with COVID-19. See the Interferons section for further discussion.
Lopinavir/Ritonavir Versus Umifenovir Versus Standard of Care
In a trial of 86 hospitalized patients with mild to moderate COVID-19, 34 patients were randomized to receive lopinavir/ritonavir, 35 patients received the broad-spectrum antiviral umifenovir (trade name Arbidol; not available in the United States), and 17 patients received standard of care.3
Results (Comparison of Lopinavir/Ritonavir to Standard of Care)
- The time to a negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid pharyngeal swab was similar for patients who received lopinavir/ritonavir (mean duration 9.0 days; SD ± 5.0 days) and for those who received standard of care (mean duration 9.3 days; SD ± 5.2 days).
- Progression to severe illness occurred among six patients (18%) in the lopinavir/ritonavir arm and two patients (12%) who received standard of care.
- Two patients became critically ill; both were randomized to receive lopinavir/ritonavir.
- The trial had a small sample size.
- The study was not blinded.
- The effectiveness of umifenovir in treating COVID-19 is unknown.
The small sample size of this trial limits its usefulness.
Lopinavir/Ritonavir Pharmacokinetics in Patients With COVID-19
In a case series, eight patients with COVID-19 were treated with lopinavir 400 mg/ritonavir 100 mg orally twice daily and had plasma trough levels of lopinavir drawn and assayed by liquid chromatography-tandem mass spectrometry.4
- The median plasma lopinavir concentration was 13.6 μg/mL.
- After correcting for protein binding, trough levels would need to be approximately 60-fold to 120-fold higher to achieve the in vitro half-maximal effective concentration (EC50) for SARS-CoV-2.
- Only the trough levels of lopinavir were quantified.
- The concentration of lopinavir required to effectively inhibit SARS-CoV-2 replication in vivo is currently unknown.
The plasma drug concentrations that were achieved using typical doses of lopinavir/ritonavir are far below the levels that may be needed to inhibit SARS-CoV-2 replication.
- Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32187464.
- Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, Phase 2 trial. Lancet. 2020;395(10238):1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401715.
- Li Y, Xie Z, Lin W, et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235585/.
- Schoergenhofer C, Jilma B, Stimpfl T, Karolyi M, Zoufaly A. Pharmacokinetics of lopinavir and ritonavir in patients hospitalized with coronavirus disease 2019 (COVID-19). Ann Intern Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32422065.