Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19

Abstract

IMPORTANCEData 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 MEASURESThe 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. RESULTSOf 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 (continued)

Efficacy and safety of hydroxychloroquine as pre-and post-exposure prophylaxis and treatment of COVID-19. Systematic review and meta-analysis of blinded, placebo-controlled, randomized clinical trials

“…Search strategy yielded 2871 potentially relevant records. After screening of titles and abstracts and evaluation of completed trials retrieved from ClinicalTrials.gov, 33 full-text articles were assessed for eligibility and 14 blinded, placebo-controlled RCTs [23][24][25][26][27][28][29][30][31][32][33][34][35][36] were included in the metaanalysis. No trials evaluating the efficacy and safety of CQ in COVID-19 were found.…”

“…No trials evaluating the efficacy and safety of CQ in COVID-19 were found. Of the included trials, four [33][34][35][36] used HCQ as a prophylactic medication pre-exposure to COVID-19, two 31,32 as a prophylactic medication post-exposure to COVID-19, three [28][29][30] as treatment for nonhospitalized patients, and five [23][24][25][26][27] as treatment for hospitalized patients with COVID-19. A flow diagram of the study selection process and specific reasons for exclusion are detailed in Figure 1.…”

“…All studies evaluating HCQ as treatment of non-hospitalized patients with COVID-19 had a low risk for selection, performance, attrition, and information bias. There was an unclear risk for detection bias in the study by Johnston et al 28 and a high risk for reporting bias in the study by Reis et al 29 due to the differences in the evaluation time of primary outcomes between trial protocol and full report. All trials were rated as a high risk of operational bias (Figure S7; supplementary file).…”

“…SARS-CoV-2 specific monoclonal antibodies (bamlanivimab, bamlanivimab with etesevimab, and casirivimab with imdevimab) have been considered in the treatment of outpatients with mild to moderate COVID-19, in the presence of high-risk criteria. [53][54][55][56][57][58] In clinical trials, HCQ has not been associated with a reduction in the prevalence, severity, or duration of COVID-19 symptoms [28][29][30] , and there is no decreased risk of hospitalization for outpatients with SARS-CoV-2 infection treated with the drug. One of the hypotheses raised for the lack of response of HCQ in the clinical trials is that patients would have achieved minimal concentrations lower than the target concentration identified from in vitro assays.…”

Immunomodulation as a Potent COVID-19 Pharmacotherapy: Past, Present and Future

“…1 However, in a meta-analysis, the chloroquine and azithromycin-treated group displayed no significant difference in mortality compared to standard care. 2 Moreover, several randomized control trials (RCTs) indicated that chloroquine with/without azithromycin was not effective in improving clinical outcomes [3][4][5] or as post-exposure prophylaxis. 6 Moreover, those drugs were associated with greater adverse effects, including the occurrence of malignant arrhythmias.…”