Lopinavir-ritonavir versus hydroxychloroquine for viral clearance and clinical improvement in patients with mild to moderate coronavirus disease 2019
Ji-Won Kim, Eun Jin Kim, Hyun Hee Kwon, Chi Young Jung, Kyung Chan Kim, Jung-Yoon Choe, M.D. Hyo-Lim Hong
The Korean Journal of Internal Medicine, doi:10.3904/kjim.2020.224
Background/Aims: The efficacies of lopinavir-ritonavir or hydroxychloroquine remain to be determined in patients with coronavirus disease 2019 . To compare the virological and clinical responses to lopinavir-ritonavir and hydroxychloroquine treatment in COVID-19 patients. Methods: This retrospective cohort study included patients with COVID-19 treated with lopinavir-ritonavir or hydroxychloroquine at a single center in Korea from February 17 to March 31, 2020. Patients treated with lopinavir-ritonavir and hydroxychloroquine concurrently and those treated with lopinavir-ritonavir or hydroxychloroquine for less than 7 days were excluded. Time to negative conversion of viral RNA, time to clinical improvement, and safety outcomes were assessed after 6 weeks of follow-up. Results: Of 65 patients (mean age, 64.3 years; 25 men [38.5%]), 31 were treated with lopinavir-ritonavir and 34 were treated with hydroxychloroquine. The median duration of symptoms before treatment was 7 days and 26 patients (40%) required oxygen support at baseline. Patients treated with lopinavir-ritonavir had a significantly shorter time to negative conversion of viral RNA than those treated with hydroxychloroquine (median, 21 days vs. 28 days). Treatment with lopinavir-ritonavir (adjusted hazard ratio [aHR], 2.28; 95% confidence interval [CI], 1.24 to 4.21) and younger age (aHR, 2.64; 95% CI 1.43 to 4.87) was associated with negative conversion of viral RNA. There was no significant difference in time to clinical improvement between lopinavir-ritonavir-and hydroxychloroquine-treated patients (median, 18 days vs. 21 days). Lymphopenia and hyperbilirubinemia were more frequent in lopinavir-ritonavir-treated patients compared with hydroxychloroquine-treated patients. Conclusions: Lopinavir-ritonavir was associated with more rapid viral clearance than hydroxychloroquine in mild to moderate COVID-19, despite comparable clinical responses. These findings should be confirmed in randomized, controlled trials.
Conflict of interest No potential conflict of interest relevant to this article was reported.
References
Anand, Ziebuhr, Wadhwani, Mesters, Hilgenfeld, Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs, Science
Bhimraj, Morgan, Shumaker, management of patients with COVID-19
Biot, Daher, Chavain, Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities, J Med Chem
Cao, Wang, Wen, A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19, N Engl J Med
Chan, Lai, Chu, Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study, Hong Kong Med J
Chen, Chan, Jiang, In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds, J Clin Virol
Chen, Liu, Liu, A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19
Chen, Zhou, Dong, Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study, Lancet
Chu, Cheng, Hung, Role of lopinavir/ ritonavir in the treatment of SARS: initial virological and clinical findings, Thorax
Da, Xue, Yi, Ban, None
De Wilde, Jochmans, Posthuma, Screening of an FDA-approved compound library identifies four smallmolecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture, Antimicrob Agents Chemother
Devaux, Rolain, Colson, Raoult, New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?, Int J Antimicrob Agents
Gautret, Lagier, Parola, Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study, Travel Med Infect Dis
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents
Hoffmann, Kleine-Weber, Schroeder, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Cell
Keyaerts, Vijgen, Maes, Neyts, Van Ranst, In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine, Biochem Biophys Res Commun
Li, Clercq, Therapeutic options for the 2019 novel coronavirus (2019-nCoV), Nat Rev Drug Discov
Lim, Jeon, Shin, Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT-PCR, J Korean Med Sci
Molina, Delaugerre, Goff, No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection, Med Mal Infect
Rajnarayanan, Dakshanamurthy, Pattabiraman, Teaching old drugs to kill new bugs": structure-based discovery of anti-SARS drugs, Biochem Biophys Res Commun
Savarino, Boelaert, Cassone, Majori, Cauda, Effects of chloroquine on viral infections: an old drug against today's diseases?, Lancet Infect Dis
Vincent, Bergeron, Benjannet, Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Virol J
Wang, Cao, Zhang, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res
Wang, Hu, Hu, Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China, JAMA
Wang, Yang, Liu, SARS coronavirus entry into host cells through a novel clathrin-and caveolaeindependent endocytic pathway, Cell Res
Yao, Ye, Zhang, In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis
Young, Ong, Kalimuddin, Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore, JAMA
Zhang, Lin, Sun, Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, Science
Zhou, Yu, Du, Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet
{ 'indexed': {'date-parts': [[2024, 5, 2]], 'date-time': '2024-05-02T14:54:39Z', 'timestamp': 1714661679979},
'reference-count': 29,
'publisher': 'Korean Association of Internal Medicine',
'issue': 'Suppl 1',
'license': [ { 'start': { 'date-parts': [[2020, 6, 16]],
'date-time': '2020-06-16T00:00:00Z',
'timestamp': 1592265600000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'http://creativecommons.org/licenses/by-nc/3.0/'}],
'funder': [ { 'DOI': '10.13039/501100016259',
'name': 'Research Institute of Medical Science, Catholic University of Daegu',
'doi-asserted-by': 'crossref'},
{'name': 'Daegu Medical Association COVID-19 scientific committee'}],
'content-domain': {'domain': ['kjim.org'], 'crossmark-restriction': True},
'published-print': {'date-parts': [[2021, 3, 1]]},
'DOI': '10.3904/kjim.2020.224',
'type': 'journal-article',
'created': {'date-parts': [[2020, 6, 15]], 'date-time': '2020-06-15T08:55:30Z', 'timestamp': 1592211330000},
'page': 'S253-S263',
'update-policy': 'http://dx.doi.org/10.3904/crossmark_policy',
'source': 'Crossref',
'is-referenced-by-count': 25,
'title': 'Lopinavir-ritonavir versus hydroxychloroquine for viral clearance and clinical improvement in '
'patients with mild to moderate coronavirus disease 2019',
'prefix': '10.3904',
'volume': '36',
'author': [ {'given': 'Ji-Won', 'family': 'Kim', 'sequence': 'first', 'affiliation': []},
{'given': 'Eun Jin', 'family': 'Kim', 'sequence': 'additional', 'affiliation': []},
{'given': 'Hyun Hee', 'family': 'Kwon', 'sequence': 'additional', 'affiliation': []},
{'given': 'Chi Young', 'family': 'Jung', 'sequence': 'additional', 'affiliation': []},
{'given': 'Kyung Chan', 'family': 'Kim', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jung-Yoon', 'family': 'Choe', 'sequence': 'additional', 'affiliation': []},
{'given': 'Hyo-Lim', 'family': 'Hong', 'sequence': 'additional', 'affiliation': []}],
'member': '2270',
'reference': [ {'key': 'ref1', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0140-6736(20)30211-7'},
{'key': 'ref2', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jama.2020.1585'},
{'key': 'ref3', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0140-6736(20)30566-3'},
{'key': 'ref4', 'volume-title': '', 'year': '2020'},
{'key': 'ref5', 'doi-asserted-by': 'publisher', 'DOI': '10.1136/thorax.2003.012658'},
{'key': 'ref6', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jcv.2004.03.003'},
{'key': 'ref7', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.03011-14'},
{'key': 'ref8', 'doi-asserted-by': 'publisher', 'DOI': '10.3346/jkms.2020.35.e79'},
{'key': 'ref9', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jama.2020.3204'},
{'key': 'ref10', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2001282'},
{'key': 'ref11', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S1473-3099(03)00806-5'},
{'key': 'ref12', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.bbrc.2004.08.085'},
{'key': 'ref13', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/1743-422X-2-69'},
{'key': 'ref14', 'doi-asserted-by': 'publisher', 'DOI': '10.1021/jm0601856'},
{'key': 'ref15', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41422-020-0282-0'},
{'key': 'ref16', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/cid/ciaa237'},
{ 'key': 'ref17',
'first-page': '215',
'volume-title': 'A pilot study of hydroxychloroquine in treatment of patients with '
'moderate COVID-19',
'author': 'Chen',
'year': '2020'},
{'key': 'ref18', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijantimicag.2020.105949'},
{'key': 'ref19', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.tmaid.2020.101663'},
{'key': 'ref20', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.medmal.2020.03.006'},
{ 'key': 'ref21',
'first-page': '399',
'volume-title': 'Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: '
'a multicentre retrospective matched cohort study',
'author': 'Chan',
'year': '2003'},
{'key': 'ref22', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/d41573-020-00016-0'},
{'key': 'ref23', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.1085658'},
{'key': 'ref24', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abb3405'},
{'key': 'ref25', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.bbrc.2004.06.155'},
{'key': 'ref26', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/cr.2008.15'},
{'key': 'ref27', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijantimicag.2020.105938'},
{'key': 'ref28', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cell.2020.02.052'},
{'key': 'ref29', 'volume-title': '', 'author': 'Bhimraj', 'year': '2020'}],
'container-title': 'The Korean Journal of Internal Medicine',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'http://kjim.org/upload/kjim-2020-224.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'http://kjim.org/journal/view.php?doi=10.3904/kjim.2020.224',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'http://kjim.org/upload/kjim-2020-224.pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2021, 3, 16]],
'date-time': '2021-03-16T04:10:04Z',
'timestamp': 1615867804000},
'score': 1,
'resource': {'primary': {'URL': 'http://kjim.org/journal/view.php?doi=10.3904/kjim.2020.224'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021, 3, 1]]},
'references-count': 29,
'journal-issue': {'issue': 'Suppl 1', 'published-print': {'date-parts': [[2021, 3]]}},
'URL': 'http://dx.doi.org/10.3904/kjim.2020.224',
'relation': {},
'ISSN': ['1226-3303', '2005-6648'],
'subject': [],
'container-title-short': 'Korean J Intern Med',
'published': {'date-parts': [[2021, 3, 1]]},
'assertion': [ { 'value': '2020-05-13',
'order': 0,
'name': 'received',
'label': 'Received',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2020-05-27',
'order': 1,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2020-06-16',
'order': 2,
'name': 'published',
'label': 'Published online',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2021-03-01',
'order': 3,
'name': 'published',
'label': 'Print publication',
'group': {'name': 'publication_history', 'label': 'Publication History'}}]}
