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
- Adverse Effects Include:
- Nausea, vomiting, diarrhea (common)
- QTc prolongation
- Lopinavir/ritonavir is a potent inhibitor of CYP3A, and many medications metabolized by this enzyme may cause severe toxicity. Please refer to the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV for a list of potential drug interactions.
Considerations in Pregnancy:
- There is wide experience with use of lopinavir/ritonavir in pregnant women with HIV, and the drug has a good safety profile.
- No evidence of human teratogenicity (can rule out a 1.5-fold increase in overall birth defects).
- 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.
- 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.
- Once daily lopinavir/ritonavir dosing 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 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.
- 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. Journal of Pharmaceutical Analysis. 2020. [In press]. Available at: https://www.sciencedirect.com/science/article/pii/S2095177920301271.
- 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.
- 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.
- 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: https://www.medrxiv.org/content/10.1101/2020.03.19.20038984v1.
- Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32236562.
- De Meyer S, Bojkova D, Cinati J, et al. Lack of antiviral activity of darunavir against SARS-CoV-2. medRxiv. 2020. [Preprint]. Available at: https://www.medrxiv.org/content/10.1101/2020.04.03.20052548v1.
- Johnson & Johnson. Lack of evidence to support use of darunavir-based treatments for SARS-CoV-2. 2020. Available at: https://www.jnj.com/lack-of-evidence-to-support-darunavir-based-hiv-treatments-for-coronavirus. Accessed May 11, 2020.