Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19
PhD; Andreas Barratt-Due, PhD Inge Christoffer Olsen, PhD Katerina Nezvalova-Henriksen, MD Trine Kåsine, PhD Fridtjof Lund-Johansen, PhD Hedda Hoel, Aleksander Rygh Holten, PhD; Anders Tveita, PhD Alexander Mathiessen, MD Mette Haugli, MD Ragnhild Eiken, PhD Anders Benjamin Kildal, PhD Åse Berg, PhD Asgeir Johannessen, PhD Lars Heggelund, Tuva Børresdatter Dahl, MSc Karoline Hansen Skåra, MD; Pawel Mielnik, Lan Ai Kieu Le, MD Lars Thoresen, MD; Dag Gernot Ernst, Dag Arne Lihaug Hoff, MD; Bård Hilde Skudal, Bård Reiakvam Kittang, Roy Bjørkholt Olsen, MD; Carl Birgitte Tholin, Carl Magnus Ystrøm, MD Nina Vibeche Skei, PhD Trung Tran, PhD Susanne Dudman, PhD Jan Terje Andersen, MD Raisa Hannula, PhD; Olav Dalgard, PhD Ane-Kristine Finbråten, PhD Kristian Tonby, PhD; Bjorn Blomberg, MD Saad Aballi, PhD Cathrine Fladeby, MSc Anne Steffensen, PhD Fredrik Müller, PhD Anne Ma Dyrhol-Riise, PhD Marius Trøseid, PhD Pål Aukrust
Annals of Internal Medicine, doi:10.7326/m21-0653
Background: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. Objective: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. Design: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials. gov: NCT04321616) Setting: 23 hospitals in Norway. Patients: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. Intervention: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). Measurements: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. Results: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance.
Limitation: The trial had no placebo group.
Conclusion: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19.
EDTA plasma samples were taken at randomization, between days 3 and 5, between days 7 and 9, and weekly thereafter. CRP, ferritin, procalcitonin, LDH, lymphocytes, and neutrophils were analyzed by the routine laboratory at the hospitals included in the study. Treatment effects are given as estimated differences in daily decrease rates (slopes) of the variables between remdesivir and its SoC during the first week, and in differences in point estimates at day 10. Results are presented as estimated treatment differences with 95% CIs. CRP = C-reactive protein; LDH = lactate dehydrogenase; SoC = standard of care. * To convert to SI units (mkat/L), multiply by 0.0167. EDTA plasma samples were taken at randomization, between days 3 and 5, between days 7 and 9, and weekly thereafter. CRP, ferritin, procalcitonin, LDH, lymphocytes, and neutrophils were analyzed by the routine laboratory at the hospitals included in the study. Treatment effects are given as estimated differences in daily decrease rates (slopes) of the variables between HCQ and its SoC during the first week, and in differences in point estimates at day 10. Results are presented as estimated treatment differences with 95% CIs. CRP = C-reactive protein; HCQ = hydroxychloroquine; LDH = lactate dehydrogenase; SoC = standard of care. * To convert to SI units (mkat/L), multiply by 0.0167. Subgroup analyses evaluating the effect on viral clearance of remdesivir compared with SoC in patients with short (<7 d) and long (≥7 d)..
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