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.
The adverse effects for lopinavir/ritonavir include:
- Nausea, vomiting, diarrhea (common)
- QTc prolongation
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
- There is extensive experience with the use of lopinavir/ritonavir in pregnant women with HIV, and the drug has a good safety profile.
- There is no evidence of human teratogenicity (a 1.5-fold increase in overall birth defects can be ruled out).
- Lopinavir has low placental transfer to the fetus. Please refer to the Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States for more information.
- Lopinavir/ritonavir oral solution contains 42.4% (volume/volume) alcohol and 15.3% (weight/volume) propylene glycol and is not recommended for use during pregnancy. Please refer to the Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States for more information.
- The use of once-daily dosing for lopinavir/ritonavir is not recommended during 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.
- 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: https://www.ncbi.nlm.nih.gov/pubmed/26868298.
- 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: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156227/.
- 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: https://www.ncbi.nlm.nih.gov/pubmed/32173287.
- 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: https://www.ncbi.nlm.nih.gov/pubmed/15288617.
- 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: https://www.ncbi.nlm.nih.gov/pubmed/14985565.
- 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: https://www.ncbi.nlm.nih.gov/pubmed/32479865.
- 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.
- 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: https://www.ncbi.nlm.nih.gov/pubmed/32187464.
- 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: https://www.ncbi.nlm.nih.gov/pubmed/32671131.