Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19
MD Gilmar Reis, Eduardo Augusto Dos Santos Moreira Silva, Daniela Carla Medeiros Silva, Lehana Thabane, Gurmit Singh, Jay J H Park, Jamie I Forrest, Ofir Harari, Castilho Vitor Quirino Dos Santos, Ana Paula Figueiredo Guimarães De Almeida, Adhemar Dias De Figueiredo Neto, Leonardo Cançado Monteiro Savassi, RN Aline Cruz Milagres, Mauro Martins Teixeira, Maria Izabel Campos Simplicio, Luciene Barra Ribeiro, Rosemary Oliveira, PhD Edward J Mills
JAMA Network Open, doi:10.1001/jamanetworkopen.2021.6468
IMPORTANCE Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. OBJECTIVE To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. INTERVENTIONS Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo.
MAIN OUTCOMES AND MEASURES The primary outcomes were COVID-19-associated hospitalization and death assessed at 90 days after randomization. COVID-19-associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events.
RESULTS Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavirritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19-associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91
ARTICLE INFORMATION Author Contributions: Drs Reis and Mills had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Reis, E.
Conflict of Interest Disclosures: None reported. Funding/Support: The trial was supported by the Bill and Melinda Gates Foundation.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Dr. Reis wishes to acknowledge particularly here the role of mayors and public health authorities in Brazil (a complete list can be found in the eAppendix of Supplement 2).
The TOGETHER Investigators
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'December 5, 2020. https://dndi.org/diseases/covid-19/'},
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'unstructured': 'Clincialtrials.gov. Trial of early therapies during non-hospitalized '
'outpatient window for COVID-19 (TREATNOW). Accessed December 5, 2020. '
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'container-title': 'JAMA Network Open',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2779044/reis_2021_oi_210214_1631721378.05543.pdf',
'content-type': 'unspecified',
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'deposited': { 'date-parts': [[2021, 9, 17]],
'date-time': '2021-09-17T15:00:55Z',
'timestamp': 1631890855000},
'score': 1,
'resource': {'primary': {'URL': 'https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779044'}},
'subtitle': ['The TOGETHER Randomized Clinical Trial'],
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'issued': {'date-parts': [[2021, 4, 22]]},
'references-count': 34,
'journal-issue': {'issue': '4', 'published-print': {'date-parts': [[2021, 4, 1]]}},
'URL': 'http://dx.doi.org/10.1001/jamanetworkopen.2021.6468',
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'ISSN': ['2574-3805'],
'subject': ['General Medicine'],
'container-title-short': 'JAMA Netw Open',
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