Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial

Abstract

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.

Primary funding source: National Clinical Therapy Research in the Specialist Health Services, Norway.

Visual Abstract.. Remdesivir and Hydroxychloroquine: Effects on SARS-CoV-2 Clearance.

In an add-on study of the WHO Solidarity trial, Norwegian investigators examined the effect of remdesivir and hydroxychloroquine on the degree of clinical respiratory failure, on SARS-CoV-2 viral load in the oropharynx, and on levels of inflammatory variables in plasma or serum.

Figure 1.. Study flow diagram.

Flow chart of patients enrolled in NOR-Solidarity from 28 March to 5 October 2020; a total of 181 patients were randomly assigned to receive SoC, remdesivir + SoC, or HCQ + SoC. A total of 149 patients completed the 3 mo of follow-up. Each pairwise intention-to-treat analysis was between the remdesivir or HCQ group and its respective SoC. Some participants receiving SoC act as controls for both active treatment groups, whereas some act in one or the other, giving a partial overlap of the 2 control groups. HCQ = hydroxychloroquine; SoC = standard of care. * Excluded from the full analysis set. † Other: emigration, progression of cancer diseases.

Appendix Figure 1.. Cumulative probability plots for duration of mechanical ventilation and intensive care unit stay.

HCQ = hydroxychloroquine; SoC = standard of care.

Figure 2.. Efficacy of viral clearance by remdesivir and HCQ.

Viral measurement was done by quantitative polymerase chain reaction testing of SARS-CoV-2 in the oropharynx. Viral load is given as the log value in 1000 cells. Viral clearance is expressed as an average decrease rate during the first week after randomization. Treatment effects are given as estimated differences in daily viral decrease rates between the remdesivir or HCQ group and its respective SoC during the first week, and in differences in viral load at day 10. The number of patients under observation at each time point (days 0, 3–5, 7–9, and 12–16) is indicated separately by study group. Data are given as means and 95% CIs. HCQ = hydroxychloroquine; SoC = standard of care.

Appendix Figure 2.. Box plots of change from baseline to days 7 and 10 in viral load and P–F ratio.

Horizontal lines denote the medians, and boxes denote the 25th and 75th percentiles. The whiskers extend to the largest value but no further than 1.5 times the interquartile range. Points outside the whiskers are considered outliers. We have used values between days 5 and 9 for the day 7 change, and between days 7 and 13 for the day 10 change. HCQ = hydroxychloroquine; P–F = Po ₂–FIo ₂. * Positive values favor active treatment (HCQ or remdesivir). † Negative values favor active treatment (HCQ or remdesivir).

Figure 3.. Effect of remdesivir and HCQ on the degree of respiratory failure assessed by P–F ratio.

P–F ratios were calculated on the basis of estimated levels of Po ₂ and FIo ₂. In patients missing arterial oxygen tension, Po ₂ was approximated from peripheral O₂ saturation according to the table stated in the analysis plan. Likewise, FIo ₂ in patients not supported by mechanical ventilation, noninvasive mechanical ventilation, or high-flow oxygen therapy was approximated from supplementation of oxygen as described in the analysis plan. Treatment effects are given as estimated differences in daily P–F ratio increase rates between the remdesivir or HCQ group and its respective SoC during the first week after randomization, and in differences in P–F ratio at day 10. The number of patients under observation at each time point (days 0, 3–5, 7–9, and 12–16) is indicated separately by study group. Data are given as means and 95% CIs. HCQ = hydroxychloroquine; P–F = Po ₂–FIo ₂; SoC = standard of care.

Appendix Figure 3.. Effect of remdesivir on inflammatory markers, lymphocytes, and neutrophils.

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 (µkat/L), multiply by 0.0167.

Appendix Figure 4.. Effect of HCQ on inflammatory markers, lymphocytes, and neutrophils.

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 (µkat/L), multiply by 0.0167.

Appendix Figure 5.. Efficacy of remdesivir on viral clearance in patients with short versus long symptom duration, with high versus low baseline viral load, and with the presence or absence of SARS-CoV-2 antibodies.

Subgroup analyses evaluating the effect on viral clearance of remdesivir compared with SoC in patients with short (<7 d) and long (≥7 d) symptom duration before hospitalization (upper left), in patients with high or low viral load (defined as above or below median level, respectively) at admission to hospital (lower left), and in the presence or absence of SARS-CoV-2 antibodies to RBD (cutoff ≥5) (upper right) and nucleocapsid (cutoff ≥10) (lower right). Treatment effects are given as estimated differences in average daily viral decrease rates (slopes) during the first week, between remdesivir and SoC, for all subanalyses. Results are presented as estimated treatment differences with 95% CIs. RBD = receptor-binding domain; SoC = standard of care.

Appendix Figure 6.. Efficacy of HCQ on viral clearance in patients with short versus long symptom duration, with high versus low baseline viral load, and with the presence or absence of SARS-CoV-2 antibodies.

Subgroup analyses evaluating the effect on viral clearance of HCQ compared with SoC in patients with short (<7 d) and long (≥7 d) symptom duration before hospitalization (upper left), in patients with high or low viral load (defined as above or below median level, respectively) at admission to hospital (lower left), and in the presence or absence of SARS-CoV-2 antibodies to RBD (cutoff ≥5) (upper right) and nucleocapsid (cutoff ≥10) (lower right). Treatment effects are given as estimated differences in average daily viral decrease rates (slopes) during the first week, between HCQ and SoC, for all subanalyses. Results are presented as estimated treatment differences with 95% CIs. HCQ = hydroxychloroquine; RBD = receptor-binding domain; SoC = standard of care.

Appendix Figure 7.. Effect of remdesivir on inflammatory markers, lymphocytes, and neutrophils.

In subgroup analyses evaluating the effect of viral clearance related to age (≥60 vs. <60 y) and degree of inflammation (ferritin and CRP; levels greater than or equal to median vs. lower than median) at baseline. Treatment effects are given as estimated differences in average daily viral decrease rates (slopes) during the first week, between remdesivir and SoC, for all subanalyses. Results are presented as estimated treatment differences with 95% CIs. CRP = C-reactive protein; SoC = standard of care.

Appendix Figure 8.. Effect of HCQ on inflammatory markers, lymphocytes, and neutrophils.

In subgroup analyses evaluating the effect of viral clearance related to age (≥60 vs. <60 y) and degree of inflammation (ferritin and CRP; levels greater than or equal to median vs. lower than median) at baseline. Treatment effects are given as estimated differences in average daily viral decrease rates (slopes) during the first week, between hydroxychloroquine and SoC, for all subanalyses. Results are presented as estimated treatment differences with 95% CIs. CRP = C-reactive protein; HCQ = hydroxychloroquine; SoC = standard of care.