Should Protease Inhibitors Be Used for COVID-19?

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MOH-ACE COVID-19 RAPID REVIEW Updated 14 April 2020. First published 26 March 2020. Should protease inhibitors be used for COVID-19?

This write-up summarises a rapid evidence review of protease inhibitors for treating COVID-19. The information may be revised as new evidence emerges.

Background

Protease inhibitors developed to treat HIV infection, have previously been trialed as a treatment for patients with Severe Acute Respiratory Syndrome (SARS-CoV); however, their clinical efficacy was inconclusive.1 As SARS-CoV and COVID-19 both belong to the Coronavirus family, protease inhibitors are currently being studied as a potential antiviral treatment for COVID-19 infection. Most ongoing trials are focusing on lopinavir/ritonavir (brand names: Kaletra, Aluvia), following reports of its efficacy in a patient with COVID-19 in South Korea.2

Clinical evidence

A literature search of protease inhibitors used for treating COVID-19 was conducted on 13 April 2020.† Twenty-six clinical trials identified are currently ongoing, with results pending (Table 1). Only one clinical trial (LOTUS China) by Cao et al. and one case series by Chen et al. has published results to date.

Table 1: List of ongoing trials investigating protease inhibitors for treating COVID-19 Study identifier Study Intervention Comparator(s) Date of primary Design completion LOTUS China trial, 3 SC*, OL, Lopinavir/ritonavir Standard of care 3 February 2020 ChiCTR2000029308 phIV, RCT NCT04291729 4 SC*, OL, Danoprevir and ritonavir with or NA March 2020 phIV, NRCT without interferon atomisation NCT04307693 5 MC, OL, phII, Lopinavir/ritonavir Hydroxychloroquine May 2020 RCT sulphate NCT04286503 6 MC, OL, Carrimycin  Lopinavir/ritonavir February 2021 phIV, RCT  Arbidol  Chloroquine phosphate NCT04255017 7 SC*, SB, Lopinavir/ritonavir  Abidol hydrochloride June 2020 phIV, RCT  Oseltamivir NCT04295551 8 MC, OL, RCT Lopinavir/ritonavir Lopinavir/ritonavir with July 2020 Xiyanping injection NCT04303299 9 MC, OL, Mild COVID-19 Standard of care October 2020 phIII, RCT  Oseltamivir and chloroquine  Lopinavir/ritonavir with favipiravir  Lopinavir/ritonavir with oseltamivir

Moderate to severe COVID-19  Lopinavir/ritonavir with oseltamivir  Lopinavir/ritonavir with favipiravir  Darunavir/ritonavir with oseltamivir with chloroquine  Darunavir/ritonavir with favipiravir with chloroquine NCT04261907 10 MC, OL, RCT ASC09 with ritonavir Lopinavir/ritonavir May 2020 NCT04315948 11 MC, OL, RCT  Remdesivir Standard of care March 2023  Lopinavir/ritonavir  Lopinavir/ritonavir with interferon β-1a

† The literature search covered antiretroviral HIV-1 protease inhibitors (amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir); and hepatitis C virus NS3/4A protease inhibitors (asunaprevir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, telaprevir and danoprevir).

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MOH-ACE COVID-19 RAPID REVIEW Updated 14 April 2020. First published 26 March 2020.

NCT04275388 12 MC, OL, RCT Xiyanping injection with Lopinavir/ritonavir and May 2020 lopinavir/ritonavir and interferon-α interferon-α nebulisation nebulisation NCT04252274 13 SC*, OL, Darunavir and cobicistat Standard of care August 2020 phIII, RCT NCT04251871 14 SC*, OL, Traditional Chinese Medicines Lopinavir/ritonavir and January 2021 RCT granules, lopinavir/ritonavir and interferon-α nebulisation interferon-α nebulisation NCT04304053 15 MC, OL, Chloroquine, darunavir and Standard of care July 2020 phIII, CRCT cobicistat NCT04276688 16 SC*, OL, phII, Lopinavir/ritonavir, ribavirin and Lopinavir/ritonavir January 2022 RCT interferon β-1b NCT02735707 MC, OL,  Lopinavir/ritonavir Standard of care December 2021 2015-002340-14 phIV, ARCT  Hydroxychloroquine and REMAP-CAP: lopinavir/ritonavir COVID-19 Antiviral  Hydroxychloroquine 17, Therapy Domain  Levofloxacin 18  Hydrocortisone  Ceftriaxone  Azithromycin  Clarithromycin  Erythromycin  Amoxicillin/clavulanate  Piperacillin/tazobactam  Roxithromycin  Ceftaroline fosamil  Moxifloxacin  Oseltamivir  Anakinra  Interferon beta-1a ASID Australia New NA  Lopinavir/ritonavir Standard of care NA South Wales trial  Lopinavir/ritonavir and hydroxychloroquine  Hydroxychloroquine ISRCTN83971151 NA  Remdesivir Standard of care March 2021 SOLIDARITY 19, 20  Lopinavir/ritonavir  Lopinavir/ritonavir and interferon β-1a  Chloroquine or hydroxychloroquine NCT04330690 MC, OL,  Lopinavir/ritonavir Standard of care March 2022 SOLIDARITY- phIII, ARCT Canada 21 2020-001366-11 MC, OL,  Remdesivir Standard of care NA SOLIDARITY- Spain phIII, ARCT  Chloroquine 22  Hydroxychloroquine sulfate  Lopinavir/ritonavir  Interferon-beta-1a NCT04321993 23 OL, phII,  Lopinavir/ritonavir Standard of care February 2021 NRCT  Hydroxychloroquine sulphate  Baricitinib  Sarilumab NCT04321174 24 MC, OL,  Lopinavir/ritonavir Patient cohort: standard March 2021 phIII, RCT of care Prevention cohort: no intervention 2020-000936-23 25 MC, OL,  Lopinavir/ritonavir Standard of care March 2023 phIII, ARCT  Interferon beta-1a  Remdesivir  Hydroxychloroquine 2020-001113-21 26 MC, OL,  Lopinavir/ritonavir Standard of care NA RECOVERY phIII, ARCT  Dexamethasone  Azithromycin  Hydroxychloroquine NCT04328285 27 MC, DB,  Hydroxychloroquine Placebo November 2020 phIII, RCT  Lopinavir/ritonavir NCT04331470 28 SC, OL,  Levamisole and Hydroxychoroquine and April 2020 phII/III, RCT budesonide/formoterol inhaler lopinavir/ritonavir and hydroxychoroquine and lopinavir/ritonavir NCT04328012 29 SC, DB,  Lopinavir/ritonavir Placebo January 2021 phII/III, ARCT  Hydroxychloroquine sulphate

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MOH-ACE COVID-19 RAPID REVIEW Updated 14 April 2020. First published 26 March 2020.

 Losartan 2020-001188-96 30 MC, DB,  Lopinavir/ritonavir Placebo NA phIII, RCT  Hydroxychloroquine 2020-001031-27 31 SC, OL, phIII,  Darunavir/cobicistat Patient cohort: standard NA CRCT  Hydroxychloroquine of care Prevention cohort: no intervention Abbreviations: DB, double blind; SB, single blind; MC, multicenter; OL, open label, phII, phase II; phIII, phase III; phIV, phase IV; RCT, randomised controlled trial; CRCT, cluster randomised controlled trial; ARCT, adaptive randomised controlled trial; SC, single centre; NA, not available; † None of the listed trials include Singapore as a study site. * China

The World Health Organization (WHO) has announced that it will be conducting a large, global trial (SOLIDARITY) on the four most promising therapies identified to date to treat COVID-19, including lopinavir/ritonavir. Over 70 countries are currently included in the trial, with more countries likely to be included over time. The date of primary completion is March 2021, with findings reported by December 2021.19, 20 Lopinavir/ritonavir The LOTUS China trial3 conducted in 199 patients with severe COVID-19 reported that there was no significant difference in time to clinical improvement between patients who received lopinavir/ritonavir in addition to standard care versus standard of care alone (median 16 days). There was also no significant difference in mortality between the two groups although the 28-day mortality rate was numerically lower with lopinavir/ritonavir compared with standard of care (19.2% vs 25%). Standard of care comprised supplemental oxygen, ventilation, antibiotic agents, vasopressor support, renal- replacement therapy and extracorporeal membrane oxygenation (ECMO) as necessary. The proportion of patients who experienced grade 3 or 4 adverse events were comparable between the two treatment groups (lopinavir/ritonavir: 39%, standard of care: 42%). Nearly 14% of patients receiving lopinavir/ritonavir could not complete the full 14-day course due to gastrointestinal adverse events.

The authors noted that the enrolled patients were likely to be more ill than typical patients which may have affected the results. A post-hoc analysis concluded that patients who received lopinavir/ritonavir within 12 days of symptom onset may experience faster clinical recovery and lower mortality (HR 1.25; 95%CI 1.17 to 2.05) compared to later treatment, but this finding was highly uncertain and required further research.3

Danoprevir/ritonavir A case series of 11 patients with moderate COVID-19 infection who received danoprevir/ritonavir with or without alpha-interferon nebulisation was published online by Chen et al.32 The article, which has not been peer reviewed, reported that all 11 patients recovered following 4 to 12 days of treatment with danoprevir/ritonavir. Viral nucleic acids in nasal swabs turned negative at a median of 2 days (range 1 to 8 days) and the absorption of acute exudative lesions occurred at a median of 3 days (range 2 to 4 days) after the initiation of danoprevir/ritonavir treatment. Due to the small sample size, lack of control subjects and possible selection bias, the significance of the reported outcomes is unclear and not considered generalisable to all patients. Larger randomised controlled trials are required to determine the clinical benefit of danoprevir/ritonavir for treating COVID-19.

Recommendations from professional bodies

WHO, US Centers for Disease Control and Prevention (CDC), European Medicines Agency, NHS (UK), Taiwan Centers for Disease Control, Singapore National Centre for Infectious Diseases (NCID) and governments in Australia, Canada, New Zealand and South Korea have reported that there is currently no approved targeted treatment for COVID-19 and symptom management is currently the best available option.33, 34, 35, 36, 37, 38, 39, 40, 41, 42

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MOH-ACE COVID-19 RAPID REVIEW Updated 14 April 2020. First published 26 March 2020.

Interim COVID-19 clinical guidelines from Belgium, China, France, India, Italy, Spain and Switzerland have included lopinavir/ritonavir as an option for investigational or compassionate use. Most guidelines propose lopinavir/ritonavir as a first-line treatment option for mild to moderate COVID-19 infection and as a second-line option for severe infections.43, 44, 45, 46, 47, 48 No other protease inhibitors are currently recommended.

Locally, in interim guidelines on the management of COVID-19, NCID recommend that if lopinavir/ritonavir (either alone or in combination with interferon beta-1b) is considered, it should be used in early illness (<12 days).49

Conclusion

Lopinavir/ritonavir is the most common protease inhibitor listed for investigational or compassionate use for COVID-19 in international clinical guidelines. However, current evidence on the efficacy and safety of any protease inhibitors for treating COVID-19 infection is limited. Large multinational studies are currently underway to provide more evidence on the use of protease inhibitors in patients with different levels of disease severity.

References

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MOH-ACE COVID-19 RAPID REVIEW Updated 14 April 2020. First published 26 March 2020.

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