Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19
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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.
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.
In February 2020, a World Health Organization (WHO) expert group recommended that 4 drugs approved for other indications—hydroxychloroquine (HCQ), remdesivir, ritonavir-boosted lopinavir, and interferon-β1a—should be evaluated in an international, adaptive, open-label, randomized clinical trial and compared with standard of care (SoC) in the treatment of hospitalized patients with SARS-CoV-2 infection. This initiative resulted in initiation of the WHO Solidarity trial (1). The HCQ and lopinavir groups of this trial were subsequently stopped because of reported lack of effect based on emerging external evidence from the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial, as well as internal evidence from interim analyses (2).
In October 2020, the WHO Solidarity trial consortium published interim results, reporting that all of the repurposed drugs evaluated showed little or no effect on in-hospital mortality and did not reduce the need for mechanical ventilation (1). For remdesivir, these results contrasted with those of ACTT (Adaptive COVID-19 Treatment Trial), which reported that remdesivir significantly reduced time to recovery and discharge from the hospital, in particular in patients not receiving mechanical ventilation (3).
Of major interest was whether remdesivir could affect the clinical course in patients with mild or moderate disease, where viral replication is believed to drive disease progression, as opposed to severe disease, in which inflammation seems to play a predominant role. Remdesivir is a viral RNA polymerase inhibitor shown to have antiviral effects on SARS-CoV-2 in vitro through interference with viral RNA production (4, 5). However, data on any antiviral effects of remdesivir in SARS-CoV-2–infected humans are scarce.
The NOR-Solidarity trial is an independent add-on study to the WHO Solidarity trial that evaluated the effects of HCQ and remdesivir compared with SoC in hospitalized patients with COVID-19. Here, we present the effect of remdesivir and HCQ compared with SoC on viral clearance as assessed by SARS-CoV-2 polymerase chain reaction (PCR) in oropharyngeal specimens. We also examined whether remdesivir and HCQ had any effects on inflammatory biomarkers and degree of respiratory failure.
Methods
Trial Design
NOR-Solidarity is an independent add-on trial to the WHO Solidarity trial, a large, open-label, adaptive, randomized clinical trial evaluating the effect of repurposed antiviral drugs on hospitalized patients with COVID-19. WHO Solidarity included 405 hospitals in 30 countries; 11 330 adults were randomly assigned, 2750 to remdesivir, 954 to HCQ, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to SoC. The NOR-Solidarity trial included biobanking and additional clinical and biochemistry data collection, as well as follow-up beyond the WHO Solidarity core protocol (ClinicalTrials.gov: NCT04321616).
Participants
The participants in NOR-Solidarity were recruited from 23 Norwegian hospitals. Eligibility criteria were adult patients (≥18 years) with SARS-CoV-2 infection confirmed by PCR who were admitted to the hospital ward or intensive care unit (ICU) with no anticipated transfer to a nonstudy hospital within 72 hours of inclusion. Informed consent by the study participant or legally authorized representative was provided before inclusion.
Key exclusion criteria were severe comorbid conditions with life expectancy less than 3 months, level of aspartate aminotransferase or alanine aminotransferase more than 5 times the upper limit of normal, rate-corrected QT interval greater than 470 ms, pregnancy, breastfeeding, acute occurrence of a comorbid condition in a 7-day period before inclusion, known intolerance to study drugs, participation in a potentially confounding trial, or concomitant medications interfering with the study drugs.
Randomization
Eligible patients were allocated in an equal ratio using computer randomization procedures. There were 2 separate allocation lists. The first was the global list, in which the allocation sequence was prepared by an independent statistician appointed by the international trial steering group. A secondary national list was additionally prepared as a backup if allocation according to the global list was not available. The randomization procedure ensured that a patient could be allocated only to an available treatment. The randomization lists were not stratified or blocked; thus, the randomization can be regarded as simple. The trial was open-label, without a placebo control.
Interventions
The participants were randomly assigned to the following groups: 1) local SoC; 2) SoC plus 800 mg of oral HCQ twice daily on day 1, then 400 mg twice daily up to 9 days; or 3) SoC plus 200 mg of intravenous remdesivir on day 1, then 100 mg daily up to 9 days. All study treatments were discontinued at discharge. During the study, local SoC changed as a result of the RECOVERY trial and updated WHO guidelines recommending systemic steroids for severe and critical COVID-19 (4 September 2020) (6).
Recruitment
NOR-Solidarity started recruiting patients on 28 March 2020, as the first study site within the WHO Solidarity trial. Patients were initially randomly assigned to HCQ or SoC. Randomization to remdesivir started on 7 April. Hydroxychloroquine was removed as a treatment group after advice from the NOR-Solidarity steering committee on 8 June 2020 because of lack of evidence of its effectiveness, confirmed in both internal WHO interim analyses and an external report from the RECOVERY study (7, 8). Thus, from 8 June 2020 on, NOR-Solidarity allocated patients only to SoC and remdesivir. On 4 October 2020, the WHO Solidarity trial consortium published interim results reporting that HCQ and remdesivir, as well as the other repurposed drugs in the trial, had little or no effect on in-hospital mortality. Whereas the remdesivir group was continued in the WHO Solidarity trial, it was stopped in the NOR-Solidarity study on 5 October because of general low mortality in hospitalized patients in Norway; the potential for adverse effects in ventilated patients; and potentially little, if any, effect of remdesivir in patients with mild disease. This decision was supported by the independent national data monitoring and safety committee.
Outcomes
The primary outcome of NOR-Solidarity was all-cause, in-hospital mortality with study treatment compared with SoC. Secondary outcomes were receipt of invasive mechanical ventilation, time to first receipt and duration of mechanical ventilation, receipt and duration of treatment at an ICU, and occurrence of suspected unexpected serious adverse reactions. Because NOR-Solidarity was an add-on trial to WHO Solidarity, most of these data have already been published as part of this report (1) but are now presented separately.
Further substudy-specific secondary outcomes included viral clearance as assessed by SARS-CoV-2 PCR in oropharyngeal specimens (measured at baseline, days 3 to 5, days 7 to 9, and thereafter every third day). Respiratory failure, as assessed by Po2–FIo2 (P–F) ratio and inflammatory laboratory variables (that is, C-reactive protein [CRP], procalcitonin, lactate dehydrogenase, and ferritin levels and lymphocyte and neutrophil counts) measured daily during hospitalization, was an additional prespecified secondary end point. Details are presented in the protocol and statistical analysis plan (Supplement).
The exploratory objective of identifying potential determinants of individual treatment responses by relating viral clearance to demographic and clinical characteristics (that is, age and time since symptom onset), baseline viral load, inflammatory markers (that is, CRP and ferritin), and levels of anti–SARS-CoV-2 antibodies with affinity to either receptor-binding domain or nucleocapsid antigen.
Statistical Analysis
Following the WHO core protocol, no sample size was prespecified.
Before the database was locked, and deliberately without knowledge of allocation, a statistical analysis plan was written and approved, prespecifying and detailing all analyses (Supplement). Because this is an add-on study, there are no adjustments for multiple testing. Interpretations of results are based on unadjusted CIs. All treatment comparisons are with concurrent controls. Thus, some participants receiving SoC act as controls for both active treatment groups, whereas some act in one or the other.
We used the log-rank statistic to test the null hypothesis of no treatment effect on all-cause mortality. The natural logarithm of the average mortality rate ratio was estimated using the (O − E)/V estimator (where O is observed events, E is expected events, and V is variance) from the log-rank statistic with 95% CIs estimated using a normal distribution with 1/V as variance. Hazard ratios, estimated using Cox proportional hazards models, were reported as advised by the journal's editors and reviewers. Because of the low number of deaths in blinded reviews, stratification variables in the primary analyses were not used. Participants who withdrew consent or were alive but still in the hospital at the time of database locking were censored at last known time of contact. Discharged participants were assumed to be alive and were censored at the time of database locking unless otherwise confirmed. Those who had an end-of-study visit at 3 months were censored at this date.
Dichotomous end points were analyzed using logistic regression without adjustment for any baseline covariates. The estimated average marginal risk difference and corresponding 95% CI were estimated using the delta method. Missing data due to discharge or participant withdrawal were imputed with best outcome. Continuous outcomes during the first 14 days were analyzed using a mixed model with fixed intercept and separate slopes before and after day 7, and random intercept and slope. The difference in slope before day 7 was used to estimate the treatment effect in the first week. We also computed the average marginal point estimate at day 10 as a separate measure of treatment difference. As sensitivity analyses, we added simpler between-group analyses using t tests and Wilcoxon tests on the change from baseline to day 7 and day 10. Subgroup analyses were done by including the subgroup as an interaction term with the treatment term in the mixed model. High and low baseline subgroups were defined by the overall median. The 90-day outcomes on antibodies against SARS-CoV-2 were analyzed using the t distribution. Durations of mechanical ventilation and ICU stay are descriptively presented using cumulative probability plots.
Methods for reverse transcriptase PCR of SARS-CoV-2 quantification and for measurement of antibodies against SARS-CoV-2 are described in Appendix 2.
All statistical analyses were done with Stata, version 16.1 (StataCorp), and R, version 4.0.3 (R Foundation), and all code is available in a public repository (https://doi.org/10.17605/OSF.IO/V8GZ6), together with the protocol and statistical analysis plan (Supplement).
Ethics
The trial protocol was approved by the regional ethics committee (118684) and by the Norwegian Medicines Agency (20/04950-23) and was overseen by an independent data and safety monitoring board. Informed consent was obtained from each patient or from the patient's legally authorized representative if the patient was not able to provide consent. Further details regarding design, overview, and analyses can be found in the protocol and statistical analysis plan (Supplement).
Role of the Funding Source
The National Clinical Therapy Research in the Specialist Health Services funded this research but had no role in design, analysis, management, interpretation of data, or preparation or approval of the manuscript, nor did it play any other conducting role.
Results
Participant Flow
From 28 March to 4 October 2020, a total of 185 patients from 23 hospitals in Norway were enrolled in the trial; according to the National Intensive Care and Pandemic Registry, this accounts for 24% of all patients hospitalized with SARS-CoV-2 in Norway during the study period (9). Four patients were excluded because of the absence of postrandomization information. Of the 181 patients who were randomly assigned, 87 were assigned to receive SoC and 97 to receive treatment with either remdesivir (n = 43) or HCQ (n = 54), with an SoC group matched to each treatment group (Figure 1). A total of 149 patients (remdesivir, n = 34; HCQ, n = 41; and SoC, n = 74) completed the 3 months of follow-up, whereas 32 patients were lost to follow-up because of death (n = 12); voluntary discontinuation (n = 7); other reasons, including emigration or progression of underlying cancer (n = 7); or unknown reasons (n = 6) (Figure 1). Not all variables were available in all patients, and missing data on patient characteristics and baseline values are reported in Appendix Table 1.
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.
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The baseline demographic and disease characteristics were generally balanced among the treatment groups (Table 1). However, the percentage of patients with a P–F ratio less than 40 kPa was higher in the remdesivir and HCQ groups than in their respective SoC groups, whereas the percentage that used angiotensin-converting enzyme inhibitors was lower in the 2 treatment groups. Most of the patients were men (65.7%), and the mean age was 59.8 years. On average, patients were hospitalized within 8 days of symptom onset. Forty-three percent had respiratory failure (that is, P–F ratio <40 kPa). At hospital admittance, SARS-CoV-2 antibodies to receptor-binding domain were present in 47% of patients and antibodies to nucleocapsid antigen in 39.4% of patients. Median treatment duration was 5 days (interquartile range [IQR], 3 to 9 days) for remdesivir and HCQ and 6 days (IQR, 3 to 9 days) for SoC, and the patients received a median total dose of 700 mg (IQR, 500 to 1050 mg) of remdesivir and 5400 mg (IQR, 3500 to 8500 mg) of HCQ. Most of the patients were discharged home (n = 137), whereas 25 were discharged to a convalescence stay or nursing home (Appendix Table 2).
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Primary and Secondary Efficacy Outcome Shared With the WHO Solidarity Trial
All-cause, in-hospital mortality was 6.6%, considerably lower than the overall mortality in the WHO Solidarity trial (11.8%). Nonetheless, no differences in mortality, including in-hospital mortality and mortality at 28 days or 60 days, were seen between the remdesivir or HCQ group and its respective SoC group (Table 2). Note, however, that the sample size was low, and a corresponding trial would have required a true treatment difference of 21% to reach 80% power.
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Like the WHO Solidarity study, we found no effects of remdesivir or HCQ on the rate of ICU admission, use of mechanical ventilation during hospitalization, or time to receipt of mechanical ventilation (Table 2). Duration of ICU stay and mechanical ventilation, reported as cumulative probability plots, also showed no differences between the treatments (Appendix Figure 1).
HCQ = hydroxychloroquine; SoC = standard of care.
Two patients in the HCQ group developed a prolonged rate-corrected QT interval, and the treatment was withdrawn. Most other serious adverse events were related to respiratory failure and interpreted as attributable to disease progression (Appendix Table 3). One suspected unexpected serious adverse reaction was reported in the remdesivir group (Appendix Table 3).
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Secondary End Points Specific to the NOR-Solidarity Trial
The most important secondary outcome in the NOR-Solidarity trial was viral load in the oropharynx. There was a general marked decrease in SARS-CoV-2 oropharyngeal load during the first week after randomization, with a similar decrease and levels after 10 days in the remdesivir, HCQ, and SoC groups (Figure 2). The differences between the treatment groups regarding the decrease rate during the first week and at day 10 were nominally in favor of SoC, with CIs excluding major effects on viral clearance for both active treatments. For sensitivity analyses, including box plots, see Appendix Figure 2.
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.
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 = Po2–FIo2.
* Positive values favor active treatment (HCQ or remdesivir).
† Negative values favor active treatment (HCQ or remdesivir).
All groups of patients had improved respiratory function, reflected by an increase in P–F ratio, during the first week after randomization. However, the rate of improvement during the first 7 days was significantly (but only modestly) improved by remdesivir but not by HCQ compared with their SoC groups. At day 10, P–F ratio was not affected in any of the intervention groups compared with the SoC groups (Figure 3).
P–F ratios were calculated on the basis of estimated levels of Po2 and FIo2. In patients missing arterial oxygen tension, Po2 was approximated from peripheral O2 saturation according to the table stated in the analysis plan. Likewise, FIo2 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 = Po2–FIo2; SoC = standard of care.
The patient group as a whole was at baseline characterized by markedly elevated plasma levels of CRP and ferritin, whereas they had decreased lymphocyte counts (Table 1). However, except for significantly more rapid decreases in levels of ferritin (both remdesivir and HCQ), lactate dehydrogenase (remdesivir), and procalcitonin (remdesivir) during the first week after randomization, and a significant lower CRP level in the remdesivir group (but higher in the HCQ group at day 10), the treatments had no marked or consistent effects on these inflammatory markers (Appendix Figures 3 and 4).
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.
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.
It could be hypothesized that the effect of remdesivir or HCQ on viral load would be dependent on symptom duration before hospitalization (≥7 vs. <7 days), the presence of SARS-CoV-2 antibodies, or high or low viral load at hospital admission. Of note, in these subgroup analyses, remdesivir did not exert any increased oropharyngeal viral clearance compared with SoC (Appendix Figure 5). Results were similar for HCQ (Appendix Figure 6). In addition, in subgroup analyses evaluating age (≥60 vs. <60 years) and degree of inflammation (ferritin and CRP; levels greater than or equal to median vs. lower than median) at baseline, we did not find any significant treatment effects on viral clearance by either remdesivir or HCQ versus its respective SoC (Appendix Figures 7 and 8).
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.
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.
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.
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.
Discussion
Recently published results of the WHO Solidarity study indicated that neither remdesivir nor HCQ had any effect on mortality, the need for mechanical ventilation, or duration of hospital stay (1). The analyses of the NOR-Solidarity trial are consistent with the main findings of that report. In addition, we found no significant effects of either remdesivir or HCQ on the rate of SARS-CoV-2 clearance in oropharyngeal samples. This lack of antiviral effect was also corroborated when examining the influence of relevant baseline characteristics, such as age, symptom duration, degree of viral load, and presence of antibodies against SARS-CoV-2.
In addition to a large difference in sample size and only remdesivir and HCQ used as active treatment groups in NOR-Solidarity, the main difference between the trials was substantially lower mortality in the NOR-Solidarity trial (6.6% vs. 11.8% after 28 days). However, mortality in NOR-Solidarity was equal to that in data from the National Intensive Care and Pandemic Registry (9). In Norway, lockdown policies were effectively introduced during the initial phase of the pandemic, reducing pressure on hospital and health care systems, which may explain the lower mortality—in particular, the favorably lower ICU mortality (18.4%)—than in other countries (10). Some differences in the presence of comorbid conditions (for example, diabetes [25% vs. 17.2%] and chronic heart disease [21% vs. 15.6%], from WHO Solidarity vs. NOR-Solidarity, respectively) (1) could also have contributed to lower mortality in the NOR-Solidarity population. Nevertheless, we found no effect on mortality, rate of ICU admission, or need for mechanical ventilation, which was consistent with the overall results of the WHO Solidarity study.
Despite the early emergence of reports that both remdesivir and HCQ effectively exerted strong antiviral activities against SARS-CoV-2 in preclinical models (11), our results show no antiviral effects of these drugs in hospitalized patients. Previously, Wang and colleagues (12) found no effect on SARS-CoV-2 clearance in 155 hospitalized patients receiving remdesivir compared with 78 patients receiving placebo. Moreover, Lyngbakken and colleagues (13) showed no antiviral effects of HCQ in 27 hospitalized patients compared with 26 patients receiving SoC. It has been claimed that these antiviral drugs, and in particular remdesivir, could be important in the early stages of COVID-19, before clinical progression to a state of hyperinflammation (14). However, we found no significant antiviral effects of remdesivir or HCQ, even in patients with symptom duration less than 7 days or baseline CRP and ferritin levels below median levels in the patient cohort. Moreover, the presence of SARS-CoV-2 antibodies or high or low viral load at hospital admission did not influence the potential antiviral effects of these drugs. Much focus has been directed at the use of remdesivir in hospitalized patients with moderate COVID-19, but the present data suggest that only a study of even earlier intervention (that is, in an outpatient, primary care setting), if any, would be warranted to rule out any antiviral effects of remdesivir in patients with COVID-19. Our data underscore the gap between preclinical and clinical studies on remdesivir (15).
The widespread use of HCQ in the first phase of the pandemic came to a quick halt after negative results in several large trials. First the RECOVERY trial and later the WHO Solidarity study demonstrated lack of any material benefit of this drug in the treatment of COVID-19 (1, 2). Despite concerns about cardiac toxicity related to the loading dose of HCQ (16), we observed no grade 4 adverse effects related to either HCQ or remdesivir, although 2 patients in the HCQ group developed a prolonged rate-corrected QT interval resulting in treatment withdrawal. However, the number of patients included in this trial was too small to adequately address safety issues.
The study has both strengths and limitations. Strengths include participation of most hospitals in Norway, ensuring enrollment of a large proportion of the patients who were hospitalized during the study period. Because this was a pragmatic trial in a real-world clinical setting, our results may be generalizable to similar patient populations. However, the study also has many limitations. Despite being a randomized controlled trial with blinded analyses of all relevant data, it did not include a placebo group. Relatively few patients were included, and CIs were wide enough to include moderate effects. Our conclusion, and particularly our subgroup analyses, should therefore be interpreted with caution. Not all data were available from all patients at all time points. Finally, patients were discharged from the hospital at the discretion of the treating physician. Accordingly, the median duration of hospitalization was 5 to 6 days, and most of the patients did not receive the full treatment length of the tested medication, although recent studies have found no statistically significant difference between a 5-day course and a 10-day course of remdesivir (17).
In conclusion, the overall lack of effect of remdesivir and HCQ on the clinical course of patients hospitalized for COVID-19 was accompanied by a paucity of effect on SARS-CoV-2 viral clearance in the oropharynx. Our findings question the antiviral potential of these drugs in hospitalized patients with COVID-19.
Appendix 1: Members of the NOR-Solidarity Trial
Members of the NOR-Solidarity Trial Who Authored This Work
Andreas Barratt-Due, Oslo University Hospital, Oslo
Inge Christoffer Olsen, Oslo University Hospital, Oslo
Katerina Nezvalova-Henriksen, Oslo University Hospital and Hospital Pharmacies, South-Eastern Norway Enterprise, Oslo
Trine Kåsine, Oslo University Hospital, Oslo
Fridtjof Lund-Johansen, Oslo University Hospital and ImmunoLingo Convergence Centre, University of Oslo, Oslo
Hedda Hoel, Institute of Clinical Medicine and Research Institute of Internal Medicine, Oslo University Hospital, and Lovisenberg Diaconal Hospital, Oslo
Aleksander Rygh Holten, Institute of Clinical Medicine, Oslo University Hospital, Oslo
Anders Tveita, Bærum Hospital, Vestre Viken Hospital Trust, Drammen
Alexander Mathiessen, Diakonhjemmet Hospital, Oslo
Mette Haugli, Sørlandet Hospital SSK, Kristiansand
Ragnhild Eiken, Innlandet Hospital Trust, Lillehammer
Anders Benjamin Kildal, University Hospital of North Norway, Tromsø
Åse Berg, Stavanger University Hospital, Stavanger
Asgeir Johannessen, Institute of Clinical Medicine, Oslo University Hospital, Oslo, and Vestfold Hospital Trust, Tønsberg
Lars Heggelund, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, and University of Bergen, Bergen
Tuva Børresdatter Dahl, Research Institute of Internal Medicine, Oslo University Hospital, Oslo
Karoline Hansen Skåra, Research Institute of Internal Medicine, Oslo University Hospital, Oslo
Pawel Mielnik, Førde Central Hospital, Førde
Lan Ai Kieu Le, Haugesund Hospital, Haugesund
Lars Thoresen, Ringerike Hospital, Vestre Viken Hospital Trust, Ringerike
Gernot Ernst, Kongsberg Hospital, Vestre Viken Hospital Trust, Drammen
Dag Arne Lihaug Hoff, Ålesund Hospital, Møre and Romsdal Hospital Trust, Ålesund
Hilde Skudal, Telemark Hospital Trust, Skien
Bård Reiakvam Kittang, Haraldsplass Deaconess Hospital, Bergen
Roy Bjørkholt Olsen, Sorlandet Hospital, Arendal
Birgitte Tholin, Molde Hospital, Møre and Romsdal Hospital Trust, Molde
Carl Magnus Ystrøm, Innlandet Hospital Trust, Elverum
Nina Vibeche Skei, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger
Trung Tran, Oslo University Hospital, Oslo
Susanne Dudman, Institute of Clinical Medicine, Oslo University Hospital, Oslo
Jan Terje Andersen, Institute of Clinical Medicine, Oslo University Hospital, Oslo
Raisa Hannula, Trondheim University Hospital, Trondheim
Olav Dalgard, Institute of Clinical Medicine, Oslo University Hospital, Oslo, and Akershus University Hospital, Lørenskog
Ane-Kristine Finbråten, Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo
Kristian Tonby, Institute of Clinical Medicine, Oslo University Hospital, Oslo
Bjorn Blomberg, Haukeland University Hospital and University of Bergen, Bergen
Saad Aballi, Østfold Hospital Kalnes, Grålum
Cathrine Fladeby, Oslo University Hospital, Oslo
Anne Steffensen, Institute of Clinical Medicine, Oslo University Hospital, Oslo
Fredrik Müller, Institute of Clinical Medicine, Oslo University Hospital, Oslo
Anne Ma Dyrhol-Riise, Institute of Clinical Medicine, Oslo University Hospital, Oslo
Marius Trøseid, Institute of Clinical Medicine, Oslo University Hospital, Oslo
Pål Aukrust, Institute of Clinical Medicine and Research Institute of Internal Medicine, Oslo University Hospital, Oslo
Members of the NOR-Solidarity Trial Who Contributed to This Work but Did Not Author It
Jorunn Brynhildsen, Østfold Hospital, Kalnes
Waleed Ghanima, Østfold Hospital, Kalnes
Lise Tuset Gustad, Nord-Trøndelag Hospital Trust/NTNU
Anne Marie Halstensen, Østfold Hospital, Kalnes
Liv Hesstvedt, Oslo University Hospital, Oslo
Mona Holberg-Petersen, Oslo University Hospital, Oslo
Synne Jenum, Oslo University Hospital, Oslo
Simreen Kaur Johal, Oslo University Hospital, Oslo
Anette Kolderup, Oslo University Hospital, Oslo
Reidar Kvåle, Haukeland University Hospital, Bergen
Nina Langeland, Haukeland University Hospital, Bergen
Ravinea Manotheepan, Diakonhjemmet Hospital, Oslo
Kristin Mohn, Haukeland University Hospital, Bergen
Richard Alexander Molvik, Innlandet Hospital Trust, Elverum
Karl Erik Müller, Vestre Viken Hospital Trust, Drammen
Lena Bugge Nordberg, Diakonhjemmet Hospital, Oslo
Hans Schmidt Rasmussen, Diakonhjemmet Hospital, Oslo
Dag Henrik Reikvam, Oslo University Hospital, Oslo
Kjerstin Røstad, Oslo University Hospital, Oslo
Lars Mølgaard Saxhaug, Nord-Trøndelag Hospital Trust/NTNU
Vegard Skogen, University Hospital of North Norway
Grethe-Elisabeth Stenvik, Diakonhjemmet Hospital, Oslo
Birgitte Stiksrud, Oslo University Hospital, Ullevål
Ruth Foseide Thorkildsen, Diakonhjemmet Hospital, Oslo
Leif Erik Vinge, Diakonhjemmet Hospital, Oslo
Eline Brenno Vaage, Oslo University Hospital, Ullevål
Bjørn Åsheim-Hansen, Vestfold Hospital Trust, Tønsberg
Appendix 2: Materials and Methods
RNA Extraction, Reverse Transcriptase PCR, and SARS-CoV-2 Quantification
Total nucleic acids were extracted from 200-µL oropharyngeal samples (MagNA Pure 96 system, MagNA Pure 96 DNA and Viral NA Small Volume Kit; Roche), and eluted in 100 µL. Bacteriophage MS2 RNA (Merck, Sigma-Aldrich) was added before extraction as an internal control. SARS-CoV-2 RNA real-time reverse transcriptase PCR targeting the viral envelope gene was done as described by Corman and colleagues (18), using MS2 primers according to Dreier and colleagues (19), on the AriaDx PCR instrument (Agilent Technologies). The quality and cellular quantification of oropharyngeal samples were analyzed using the CELL Control r-gene kit (bioMérieux) according to the manufacturers' instructions. Viral load was calculated using standard dilution series of purified RNA from the Frankfurt1 strain, provided by the European Virus Archive Global. Viral loads for respiratory samples were normalized according to the cellular quantification as log10 RNA copies per 1000 cells.
Measurement of Antibodies Against SARS-CoV-2
A multiplexed, bead-based, flow cytometric assay, called microsphere affinity proteomics, was adapted for detection of SARS-CoV-2 antibodies (20). Thus, amine-functionalized polymer beads were color-coded with fluorescent dyes, as described earlier, and reacted successively with amine-reactive biotin (Sulfo-NHS-LC-Biotin, Proteochem) and NeutrAvidin (Thermo Fisher). A DNA construct encoding the receptor-binding domain of spike-1 protein from SARS-CoV-2 was provided by Florian Krammer, and the described protocol was used to produce recombinant protein in Expi293F cells (Thermo Fisher) (21). Bacterially expressed full-length nucleocapsid from SARS-CoV-2 was purchased from Prospec Bio (www.prospecbio.com). Viral proteins solubilized in phosphate-buffered saline were biotinylated chemically using a 4:1 molar ratio of Sulfo-NHS-LC-Biotin to protein. Free biotin was removed using G50 Sephadex spin columns. Biotinylated proteins were bound to NeutrAvidin-coupled microspheres with fluorescent barcodes. Beads with NeutrAvidin only were used as reference for background binding. Sera were diluted 1:1000 in phosphate-buffered saline containing 1% Tween 20, 1% bovine serum albumin, 10 μg/mL d-biotin, and 10 μg/mL NeutrAvidin (Thermo Fisher) and were incubated with a mixture of antigen-coupled and NeutrAvidin-only beads for 1 hour at 22 °C under constant agitation. The beads were washed twice in PBT, labeled with R-phycoerythrin–conjugated goat anti-human IgG-Fc (Jackson Immunoresearch) for 20 minutes, washed again, and analyzed by flow cytometry (Attune NxT, Thermo Fisher). Specific binding was measured as the ratio of R-phycoerythrin fluorescence intensity of antigen-coupled beads and NeutrAvidin-only beads, with a ratio of 5 and 10 defining the cutoff for a positive antibody against RBP and nucleocapsid, respectively. Reference panels containing samples from 287 individuals with PCR-confirmed SARS-CoV-2 infection and 1343 prepandemic samples were used to set the cutoff. With a cutoff set to obtain a specificity of 100%, the sensitivity was 84%, and 92% when including borderline values.
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Acknowledgment: The authors thank WHO Solidarity for the opportunity to take part and to join this global trial as an add-on study. They thank the National Clinical Therapy Research in the Specialist Health Services (KLINBEFORSK), Norway, for providing support, thus facilitating a national project including many hospitals.
Financial Support: By National Clinical Therapy Research in the Specialist Health Services (project 2020201).
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-0653.
Data Sharing Statement: The following data will be made available with publication: deidentified participant data (contact Andreas Barratt-Due; e-mail, andreas.
Corresponding Author: Andreas Barratt-Due, PhD, Division of Emergencies and Critical Care, Oslo University Hospital Rikshospitalet, N-0027 Oslo, Norway; e-mail, andreas.
Current Author Addresses: Drs. Barratt-Due, I.C. Olsen, Nezvalova-Henriksen, Kåsine, Lund-Johansen, Holten, Tran, Dudman, Andersen, Tonby, Fladeby, Müller, Dyrhol-Riise, Trøseid, and Aukrust; Ms. Skåra; and Ms. Steffensen: Oslo University Hospital, Postboks 4956 Nydalen, 0424 Oslo, Norway.
Dr. Hoel: Lovisenberg Diaconal Hospital, Postboks 4970 Nydalen, 0424 Oslo, Norway.
Drs. Tveita, Heggelund, and Ernst: Vestre Viken Hospital Trust, Postboks 800, 3004 Drammen, Norway.
Dr. Mathiessen: Diakonhjemmet Hospital, Postboks 23 Vindern, 0319 Oslo, Norway.
Dr. Haugli: Sorlandet Hospital SSK, Postboks 419 Lundsiden, 4604 Kristiansand, Norway.
Dr. Eiken: Innlandet Hospital Trust Anders Sandvigs Gate 7, 2609 Lillehammer, Norway.
Dr. Kildal: University Hospital of North Norway, Sykehusvegen 38, 9019 Tromsø, Norway.
Dr. Berg: Stavanger University Hospital, Postboks 8100, 4068 Stavanger, Norway.
Dr. Johannessen: Vestfold Hospital Trust, Postboks 2168, 3103 Tønsberg, Norway.
Dr. Dahl: Oslo University Hospital, Postboks 4970 Nydalen, 0424 Oslo, Norway.
Dr. Mielnik: Helse Førde, Svanehaugvegen 2, 6812 Førde, Norway.
Dr. Le: Haugesund Hospital, Karmsundgata 120, 5528 Haugesund, Norway.
Dr. Thoresen: Vestre Viken Hospital Trust, Arnhold Dybjords vei 1, 3511 Hønefoss, Norway.
Dr. Hoff: Ålesund Hospital Åse, 6026 Ålesund, Norway.
Dr. Skudal: Telemark Hospital Trust, Postboks 2900, 3710 Skien, Norway.
Dr. Kittang: Haraldsplass Deaconess Hospital, Postboks 6165, 5892 Bergen, Norway.
Dr. R.B. Olsen: Sorlandet Hospital, Arendal Box 416, Lundsiden, 4604 Kristiansand, Norway.
Dr. Tholin: Molde Hospital, Parkvegen 84 6412 Molde, Norway.
Dr. Ystrøm: Innlandet Hospital Trust, Kirkeveien 31, 2409 Elverum, Norway.
Dr. Skei: Nord-Trøndelag Hospital Trust/NTNU, Postboks 333, 7601 Levanger, Norway.
Dr. Hannula: Trondheim University Hospital, Postboks 3250 Torgarden, 7006 Trondheim, Norway.
Dr. Dalgard: Akershus University Hospital, 1478 Lørenskog, Norway.
Dr. Finbråten: Lovisenberg Diaconal Hospital, Lovisenberggata 17, 0456 Oslo, Norway.
Dr. Blomberg: Haukeland University Hospital, Jonas Lies veg 65, 5021 Bergen, Norway.
Dr. Aballi: Østfold Hospital PB 300, 1714 Grålum, Norway.
Author Contributions: Conception and design: A. Barratt-Due, I.C. Olsen, K. Nezvalova-Henriksen, T. Kåsine, A. Mathiessen, A.B. Kildal, Å. Berg, A. Johannessen, P. Mielnik, R.B. Olsen, T. Tran, S. Dudman, F. Müller, M. Trøseid, P. Aukrust.
Analysis and interpretation of the data: A. Barratt-Due, I.C. Olsen, F. Lund-Johansen, M. Haugli, Å. Berg, L. Heggelund, T.B. Dahl, P. Mielnik, R.B. Olsen, T. Tran, S. Dudman, J.T. Andersen, R. Hannula, K. Tonby, B. Blomberg, C. Fladeby, A. Steffensen, F. Müller, A.M. Dyrhol-Riise, M. Trøseid, P. Aukrust.
Drafting of the article: A. Barratt-Due, I.C. Olsen, K. Nezvalova-Henriksen, F. Lund-Johansen, Å. Berg, P. Mielnik, L.A.K. Le, G. Ernst, D.A.L. Hoff, R.B. Olsen, N.V. Skei, S. Dudman, A. Steffensen, M. Trøseid, P. Aukrust.
Critical revision of the article for important intellectual content: A. Barratt-Due, I.C. Olsen, K. Nezvalova-Henriksen, T. Kåsine, F. Lund-Johansen, H. Hoel, A.R. Holten, A. Tveita, A. Mathiessen, M. Haugli, A.B. Kildal, Å. Berg, A. Johannessen, L. Heggelund, T.B. Dahl, P. Mielnik, L.A.K. Le, L. Thoresen, D.A.L. Hoff, B.R. Kittang, R.B. Olsen, B. Tholin, N.V. Skei, S. Dudman, J.T. Andersen, R. Hannula, O. Dalgard, C. Fladeby, A. Steffensen, F. Müller, A.M. Dyrhol-Riise, M. Trøseid, P. Aukrust.
Final approval of the article: A. Barratt-Due, I.C. Olsen, K. Nezvalova-Henriksen, T. Kåsine, F. Lund-Johansen, H. Hoel, A.R. Holten, A. Tveita, A. Mathiessen, M. Haugli, R. Eiken, A.B. Kildal, Å. Berg, A. Johannessen, L. Heggelund, T.B. Dahl, K.H. Skåra, P. Mielnik, L.A.K. Le, L. Thoresen, G. Ernst, D.A.L. Hoff, H. Skudal, B.R. Kittang, R.B. Olsen, B. Tholin, C.M. Ystrøm, N.V. Skei, T. Tran, S. Dudman, J.T. Andersen, R. Hannula, O. Dalgard, A.K. Finbråten, K. Tonby, B. Blomberg, S. Aballi, C. Fladeby, A. Steffensen, F. Müller, A.M. Dyrhol-Riise, M. Trøseid, P. Aukrust.
Provision of study materials or patients: K. Nezvalova-Henriksen, H. Hoel, A. Tveita, M. Haugli, Å. Berg, A. Johannessen, L. Heggelund, P. Mielnik, G. Ernst, D.A.L. Hoff, B.R. Kittang, R.B. Olsen, B. Tholin, S. Dudman, O. Dalgard, A.K. Finbråten, K. Tonby, B. Blomberg, S. Aballi, A.M. Dyrhol-Riise.
Statistical expertise: I.C. Olsen.
Obtaining of funding: A. Barratt-Due, L. Heggelund, M. Trøseid, P. Aukrust.
Administrative, technical, or logistic support: A. Barratt-Due, I.C. Olsen, K. Nezvalova-Henriksen, T. Kåsine, A.R. Holten, A. Tveita, A. Mathiessen, A.B. Kildal, Å. Berg, L. Heggelund, T.B. Dahl, P. Mielnik, G. Ernst, D.A.L. Hoff, H. Skudal, R.B. Olsen, N.V. Skei, J.T. Andersen, R. Hannula, S. Aballi, A. Steffensen, F. Müller, A.M. Dyrhol-Riise, M. Trøseid.
Collection and assembly of data: A. Barratt-Due, K. Nezvalova-Henriksen, T. Kåsine, F. Lund-Johansen, H. Hoel, A.R. Holten, A. Tveita, A. Mathiessen, M. Haugli, R. Eiken, A.B. Kildal, Å. Berg, A. Johannessen, L. Heggelund, K.H. Skåra, P. Mielnik, L.A.K. Le, L. Thoresen, G. Ernst, D.A.L. Hoff, H. Skudal, B.R. Kittang, R.B. Olsen, C.M. Ystrøm, N.V. Skei, R. Hannula, O. Dalgard, A.K. Finbråten, K. Tonby, B. Blomberg, C. Fladeby, A. Steffensen, A.M. Dyrhol-Riise, P. Aukrust.
Previous Posting: This manuscript was posted as a preprint on SSRN on 11 February 2021. doi:10.2139/ssrn.3774182
This article was published at Annals.org on 13 July 2021.
* For members of the NOR-Solidarity trial, see Appendix 1.
Response: The Importance of studies evaluating early intervention
We appreciate the comments from Ngo et al. concerning our recent article in Ann Intern Med (1). Whereas the clinical effects of treatment studies, preferentially RCTs, are clearly the most important, studies based on bio-banking, as illustrated in the NOR-Solidarity trial, are of interest because they can clarify whether a particular treatment option has or has not an effect on the disease and can elucidate novel treatment targets. In the NOR-Solidarity trial neither hydroxychloroquine nor remdesivir had any effects on inflammation or viral load. Remdesivir has been suggested to inhibit the RNA-dependent RNA polymerase of coronaviruses including SARS-CoV-2 and showed promising anti-viral effects in pre-clinical studies (2), so the lack of effects in clinical samples may seem disappointing. However, as pointed out by Ngo et al., hospitalized Covid-19 patients included in the NOR-Solidarity trial are not unlikely to be in the tail of the viral phase of the disease. We therefore clearly agree that there is an urgent need for studies testing anti-viral agents immediately after symptom debut to see whether this approach can significantly reduce the need for hospitalization. In general, and in particular during epidemics and pandemics, such drugs should be easily administered, stored and transported. Remdesivir is no such candidate. Cameostat mesylate, a serine protease inhibitor, favipiravir, an oral inhibitor of the RNA-dependent RNA polymerase and molnupiravir, a viral ribonucleoside inhibitor on the other hand are potential candidates, among many others (3). Recently, the Oxford based PRINCIPLE trial (4), as mentioned by Ngo et al., started to test the potential antiviral effect of the anti-parasitic drug ivermectin in this group of patients. The results from such studies may be of major importance both at present and during future pandemics, and could become an important supplement to vaccination.
Treatment of COVID-19 in Hospitalized Patients
This article by the Norwegian Solidarity investigators offers the detailed investigation so essential to truly understand possible benefits of treatment of COVID-19 in its many different stages.
Symptomatic COVID-19 exhibits a characteristic sequence of phases beginning with a primary viral attack, manifesting as an influenza-like illness. Then, within seven to 10 days of onset of symptoms, an inflammatory phase develops in up to 20% of
infected individuals, typically heralded by an organizing pneumonia (1). It is typically at the time of the inflammatory phase that patients are sick enough to present for hospital admission. By that time, viral loads are usually markedly decreased from the early viral phase.
The authors are to be complemented for utilizing a truly quantitative measure of viral load: RNA copies/1000 cells. Very few studies are that precise, usually presenting data as RNA copies/ml.
It should be noted that the viral loads they report are of the order of 10^3, much lower than the 10^5 to 10^8 levels initially reported by Lescure et al (2). One might conclude that the NORS-Solidarity patients described were in the tail of the viral phase of the disease, also suggested by the 7 day mean duration of symptoms, thus explaining the apparent lack of effect of the active interventions on viral load.
The focus of treatment approaches to COVID-19 thus far has been on hospitalized patients. We and others have urged a change in emphasis to the time of first diagnosis (3,4). If antiviral agents are to be effective, they should be offered to non-hospitalized patients at the time of initial PCR diagnosis. The Oxford based PRINCIPLE trials have now targeted this phase of the disease and hopefully will confirm the effectiveness of early treatment.
(1) Griffin DO, Brennan-Rieder D, Ngo B, et al. The importance of
understanding the stages of COVID-19 in treatment and trials.
AIDS Rev. 2021. DOI:10.24875/AIDSRev.200001261
(4) McCullough PA, Kelly RJ, Ruocco G, et al. Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection. Am J Med. 2021 Jan;134(1):16-22