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Lopinavir/Ritonavir and Other HIV Protease Inhibitors

Last Updated: July 17, 2020

Lopinavir/ritonavir and darunavir/cobicistat have been studied in patients with COVID-19.

The replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) depends on the cleavage of polyproteins into an RNA-dependent RNA polymerase and a helicase.1 Two proteases are responsible for this cleavage: 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro).

Lopinavir/ritonavir is an inhibitor of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) 3CLpro in vitro, and this protease appears to be 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; therefore, coronavirus-infected enterocytes might be exposed to higher concentrations of the drug.5

Darunavir inhibits the 3CLpro enzyme of SARS-CoV-2 and possibly also inhibits the PLpro enzyme. However, in an in vitro study, darunavir did not show activity against SARS-CoV-2.6


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


The pharmacodynamics of lopinavir/ritonavir raise concerns about whether it is possible to achieve drug concentrations that can inhibit the SARS-CoV-2 proteases. In addition, lopinavir/ritonavir did not show efficacy in a moderately sized randomized controlled trial in patients with COVID-19.

Adverse Effects

The adverse effects for lopinavir/ritonavir include:

  • Nausea, vomiting, diarrhea (common)
  • QTc prolongation
  • Hepatotoxicity

Drug-Drug Interactions

Lopinavir/ritonavir is a potent inhibitor of cytochrome P450 3A. Coadministering lopinavir/ritonavir with medications that are metabolized by this enzyme may increase the concentrations of those medications, resulting in concentration-related toxicities. Please refer to the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV for a list of potential 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 using lopinavir/ritonavir to treat COVID-19 in pediatric patients.

Clinical Data for COVID -19

  • The plasma drug concentrations achieved using typical doses of lopinavir/ritonavir are far below the levels that may be needed to inhibit SARS-CoV-2 replication.7
  • A moderately sized randomized trial failed to find a virologic or clinical benefit of lopinavir/ritonavir over standard of care.8
  • Results from a small randomized controlled trial showed that darunavir/cobicistat was not effective for the treatment of COVID-19.9
  • There are no data from clinical trials that support using other HIV protease inhibitors to treat COVID-19.
  • Please see Lopinavir/Ritonavir: Selected Clinical Data for more information.


  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. J Pharm Anal. 2020;Published online ahead of print. 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. De Meyer S, Bojkova D, Cinatl J, et al. Lack of antiviral activity of darunavir against SARS-CoV-2. Int J Infect Dis. 2020;97:7-10. Available at:
  7. 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:
  8. 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;382(19):1787-1799. Available at:
  9. Chen J, Xia L, Liu L, et al. Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19. Open Forum Infect Dis. 2020. Available at: