Skip to main content

Lopinavir/Ritonavir and Other HIV Protease Inhibitors

Last Updated: May 12, 2020


  • The Panel recommends against the use of lopinavir/ritonavir (AI) or other HIV protease inhibitors (AIII) for the treatment of COVID-19, except in the context of a clinical trial.

Rationale for Recommendation:

The pharmacodynamics of HIV protease inhibitors raise concern regarding whether drug levels adequate to inhibit the SARS-CoV-2 protease can be achieved with oral dosing. Also, lopinavir/ritonavir was studied in a small randomized controlled trial in patients with COVID-19 with results that did not show efficacy (see below).


Proposed Mechanism of Action and Rationale for Use in COVID-19:

  • Replication of SARS-CoV-2 depends on the cleavage of polyproteins into an RNA-dependent RNA polymerase and a helicase.1 The enzymes responsible for this cleavage are two proteases, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro).
  • Lopinavir/ritonavir is an inhibitor of SARS-CoV 3CLpro in vitro, and this protease appears highly conserved in SARS-CoV-2.2,3
  • Although lopinavir/ritonavir has in vitro activity against SARS-CoV, it is thought to have a poor selectivity index, indicating that higher than tolerable levels of the drug might be required to achieve meaningful inhibition in vivo.4
  • Lopinavir is excreted in the gastrointestinal tract, and thus coronavirus-infected enterocytes might be exposed to higher concentrations of the drug.5

Clinical Data in COVID-19

Randomized Controlled Trial of Lopinavir/Ritonavir Versus Standard of Care

In a clinical trial that randomized 199 patients to lopinavir 400 mg/ritonavir 100 mg orally twice daily for 14 days or to standard of care (SOC), patients randomized to the lopinavir/ritonavir arm did not have a shorter time to clinical improvement.6


  • There was a lower, but not statistically significant, mortality rate for the lopinavir/ritonavir group (19.2%) than for the SOC group (25.0%) and shorter ICU stay for those in the lopinavir/ritonavir group than in the SOC group (6 days vs. 11 days; difference = -5 days; 95% CI, -9 to 0).
  • The duration of hospital stays and time to clearance of viral RNA from respiratory tract samples did not differ between the lopinavir/ritonavir and SOC arms.
  • Nausea, vomiting, and diarrhea were all more frequent in the lopinavir/ritonavir-treated group.
  • The study was powered only to show a fairly large effect.


  • The study was not blinded, which may have affected the assessments of clinical improvement.
  • The study was underpowered to show small effects.

Interpretation: A moderate-sized randomized trial failed to find a virologic or clinical benefit of lopinavir/ritonavir over standard of care.

Lopinavir/Ritonavir Versus Arbidol Versus Standard of Care

This study has not been peer reviewed.

In a trial of 86 hospitalized patients with mild-to-moderate COVID-19, 34 patients were randomized to lopinavir/ritonavir, 35 patients to the broad-spectrum antiviral Arbidol (available in Russia), and 17 patients to SOC.7

Results (Comparison of Lopinavir/Ritonavir to Standard of Care):

  • The time to a negative SARS-CoV-2 nucleic acid pharyngeal swab was similar for patients receiving lopinavir/ritonavir (mean of 9 days [SD 5.0]) and for those receiving SOC (mean of 9.3 days [SD 5.2]).
  • Progression to severe/critical status occurred among eight patients receiving lopinavir/ritonavir (24%) and two patients on SOC (12%).


  • The trial had a small sample size.
  • The effectiveness of Arbidol in treating COVID-19 is unknown.

Interpretation: The small sample size of this trial limits its usefulness.

Lopinavir/Ritonavir Versus Chloroquine

A small randomized study in China compared lopinavir/ritonavir to chloroquine. Please refer to the chloroquine section for the study description.8

Clinical Trials: None in the United States

Monitoring, Adverse Effects, and Drug-Drug Interactions

Considerations in Pregnancy:

Considerations in Children:

  • Lopinavir/ritonavir is approved for the treatment of HIV in infants, children, and adolescents.
  • There are no data on the efficacy of lopinavir/ritonavir used to treat COVID-19 in pediatric patients.

Darunavir/Cobicistat or Darunavir/Ritonavir

Rationale for Use, Proposed Mechanism of Action for COVID-19:

  • Inhibition of the 3CLpro enzyme of SARS-CoV-2 and possibly also inhibition of the PLpro enzyme.
  • In an in vitro study, darunavir did not show activity against SARS-CoV-2.9
  • Results from an unpublished randomized controlled trial of 30 patients in China showed that darunavir/cobicistat was not effective in the treatment of COVID-19.10

Clinical Trials: None in the United States

Other HIV Protease Inhibitors, Including Atazanavir

There are no data from clinical trials that support the use of other HIV protease inhibitors to treat COVID-19.


  1. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov. 2016;15(5):327-347. Available at:
  2. Tahir ul Qamar M, Alqahtani SM, Alamri MA, Chen L. Structural basis of SARS-CoV-2 3CLpro and anti-COVID-19 drug discovery from medicinal plants. Journal of Pharmaceutical Analysis. 2020. [In press]. Available at:
  3. Liu X, Wang XJ. Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. J Genet Genomics. 2020;47(2):119-121. Available at:
  4. 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(1):69-75. Available at:
  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(3):252-256. Available at:
  6. 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:
  7. Li Y, Xie Z, Lin W, et al. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv. 2020. [Preprint]. Available at:
  8. Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020. Available at:
  9. De Meyer S, Bojkova D, Cinati J, et al. Lack of antiviral activity of darunavir against SARS-CoV-2. medRxiv. 2020. [Preprint]. Available at:
  10. Johnson & Johnson. Lack of evidence to support use of darunavir-based treatments for SARS-CoV-2. 2020. Available at: Accessed May 11, 2020.