Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial

Abstract

BackgroundLopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking.ObjectiveTo determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients.DesignOpen-label, randomized, adaptive, controlled trial.SettingMulti-center trial with patients from France.Participants583 COVID-19 inpatients requiring oxygen and/or ventilatory supportInterventionStandard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-ß-1a (44 μg of subcutaneous IFN-ß-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days).MeasurementsThe primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses.ResultsAdjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE.LimitationsNot a placebo-controlled, no anti-inflammatory agents tested.ConclusionNo improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings.RegistrationNCT04315948.FundingPHRC 2020, Dim OneHealth, REACTing

Antiviral Therapeutic Approaches for SARS-CoV-2 Infection: A Systematic Review

“…The DisCoVery trial is an RCT carried out in multiple French healthcare centres simultaneously, in which several lines of treatment have been investigated [ 58 ]. While in one of the intervention arms patients were randomized to lopinavir/ritonavir in monotherapy, in another arm the patients were allocated to a combination therapy of lopinavir/ritonavir + IFN-β1a.…”

“…While in one of the intervention arms patients were randomized to lopinavir/ritonavir in monotherapy, in another arm the patients were allocated to a combination therapy of lopinavir/ritonavir + IFN-β1a. Both intervention arms were compared with a group of patients assigned to standard of care [ 58 ].…”

“…None of these investigational treatments resulted in significant clinical improvement at day 15 and at day 29, as measured on the WHO-7-point ordinal scale, where “1” implies the absence of activity limitations or need for hospitalization and “7” equals death [ 58 ].…”

“…In more detail, the odds for clinical status improvement at day 15 in the lopinavir/ritonavir monotherapy group versus the standard of care group was OR = 0.83 (95% CI = 0.55–1.26; p = 0.39), while at day 29 it was OR = 0.93 (95% CI = 0.62–1.41; p = 0.74) [ 58 ]. In the case of dual therapy (lopinavir/ritonavir+ IFN-β1a) compared to standard of care, the odds for clinical improvement at day 15 was OR = 0.69 (95% CI = 0.45–1.04; p = 0.08) and at day 29 it was OR = 0.76 (95% CI = 0.50–1.15; p = 0.19) [ 49 ].…”

“…In the case of dual therapy (lopinavir/ritonavir+ IFN-β1a) compared to standard of care, the odds for clinical improvement at day 15 was OR = 0.69 (95% CI = 0.45–1.04; p = 0.08) and at day 29 it was OR = 0.76 (95% CI = 0.50–1.15; p = 0.19) [ 49 ]. Likewise, no statistically significant differences were identified in terms of mortality, oxygenation-free days, and ventilator-free days between patients who received lopinavir/ritonavir, either in monotherapy or associated with IFN-β1a, and patients in the control group [ 58 ].…”