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• W4323320726 abstract "Article Figures and data Abstract Editor's evaluation Introduction Methods Results Discussion Appendix 1 Appendix 2 Appendix 3 Appendix 4 Data availability References Decision letter Author response Article and author information Metrics Abstract Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has clinically significant antiviral activity in vivo is uncertain. Methods: In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high-dose oral ivermectin (600 µg/kg daily for 7 days), the monoclonal antibodies casirivimab and imdevimab (600 mg/600 mg), and no study drug. The primary outcome was the comparison of viral clearance rates in the modified intention-to-treat population. This was derived from daily log10 viral densities in standardized duplicate oropharyngeal swab eluates. This ongoing trial is registered at https://clinicaltrials.gov/ (NCT05041907). Results: Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Following ivermectin, the mean estimated rate of SARS-CoV-2 viral clearance was 9.1% slower (95% confidence interval [CI] –27.2% to +11.8%; n=45) than in the no drug arm (n=41), whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster (95% CI +7.0% to +115.1%; n=10 (Delta variant) vs. n=41). Conclusions: High-dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Pharmacometric evaluation of viral clearance rate from frequent serial oropharyngeal qPCR viral density estimates is a highly efficient and well-tolerated method of assessing SARS-CoV-2 antiviral therapeutics in vitro. Funding: ‘Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)’ is supported by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. Clinical trial number: NCT05041907. Editor's evaluation This valuable clinical trial demonstrated in a convincing fashion that ivermectin does not increase the rate of SARS-CoV-2 clearance from the oral compartment. This work will be of interest to clinicians and virologists and further demonstrates the use of viral clearance rate as a possible surrogate marker for SARS-CoV-2 antiviral trials. https://doi.org/10.7554/eLife.83201.sa0 Decision letter Reviews on Sciety eLife's review process Introduction Effective, safe, well-tolerated, and inexpensive oral antiviral agents are needed for the early treatment of COVID-19. Monoclonal antibodies, mainly directed against the SARS-CoV-2 spike protein, have proved effective in preventing and treating COVID-19 (Weinreich et al., 2021; O’Brien et al., 2021), but they are expensive, require parenteral administration, and are very vulnerable to the emergence of spike protein mutations (Bruel et al., 2022). Recently, large randomized controlled trials have shown clinical efficacy in the treatment of early COVID-19 for the ribonucleoside analog molnupiravir and the protease inhibitor nirmatrelvir (in combination with ritonavir) (Jayk Bernal et al., 2022; Hammond et al., 2022), but these drugs are not yet widely available, especially in low- and middle-income settings. There have been no reported randomized comparisons between these expensive medicines. In the absence of comparative assessments, and uncertainty over antiviral efficacy, national treatment guidelines vary widely across the world. Early in the COVID-19 pandemic, considerable attention was focussed on available drugs that might have useful antiviral activity (Robinson et al., 2022). Notable and widely promoted repurposing candidates included hydroxychloroquine, remdesivir, and ivermectin. The macrocyclic lactone endectocide ivermectin was pursued after a laboratory study suggested antiviral activity against SARS-CoV-2 (Caly et al., 2020). This in vitro activity, extensive experience in mass treatments for onchocerciasis, a well-established safety profile, and claims of clinical benefit, led to ivermectin being added to COVID-19 treatment guidelines in many countries, particularly in Latin America (Mega, 2020). Several small clinical trials have reported a survival benefit for ivermectin, although the quality of these trials has been questioned (Lawrence et al., 2021). Ivermectin’s relatively weak in vitro activity in relation to achievable blood levels in vivo has argued for the evaluation of maximum tolerated doses (c.600 µg/kg/day). The large TOGETHER platform trial excluded substantial clinical benefit with ivermectin in early COVID-19 infection. This was evaluated using a composite outcome of hospitalization or lengthy (> 6 hr) emergency department visit (relative risk, 0.90; 95% Bayesian credible interval, 0.70–1.16), but the TOGETHER trial used a relatively low dose of ivermectin; 400 µg/kg/day for only 3 days (Reis et al., 2022). To resolve the uncertainty over efficacy, we measured the in vivo antiviral activity of high-dose ivermectin in previously healthy adults with early symptomatic COVID-19 infection. Methods PLATCOV is an ongoing open label, randomized, controlled adaptive platform trial designed to provide a standardized quantitative comparative method for in vivo assessment of potential antiviral treatments in early symptomatic COVID-19. The primary outcome is the change in the rate of viral clearance compared with the contemporaneous no study drug arm. This is measured as the change in the slope of the log10 oropharyngeal viral clearance curve (Watson et al., 2022). The trial was conducted in the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok; Bangplee hospital, Samut Prakarn; and Vajira hospital, Navamindradhiraj University, Bangkok, all in Thailand (see Notes). The trial was approved by local and national research ethics boards in Thailand (Faculty of Tropical Medicine Ethics Committee, Mahidol University, FTMEC Ref: TMEC 21-058) and the Central Research Ethics Committee (CREC, Bangkok, Thailand, CREC Ref: CREC048/64BP-MED34) and by the Oxford University Tropical Research Ethics Committee (OxTREC EC, Oxford, UK, OxTREC Ref: 24-21). All patients provided fully informed written consent. The trial was coordinated and monitored by the Mahidol Oxford Tropical Medicine Research Unit (MORU). The PLATCOV trial was overseen by a trial steering committee and results were reviewed by a data and safety monitoring board (DSMB). The funders had no role in the design, conduct, analysis, or interpretation of the trial. The ongoing trial is registered at https://clinicaltrials.gov/ (NCT05041907). Participants Patients presenting to the Acute Respiratory Infections outpatient clinics for COVID-19 testing were prescreened for study eligibility. Previously healthy adults aged between 18 and 50 years were eligible for the trial if they had early symptomatic COVID-19 (i.e., reported symptoms for not more than 4 days), oxygen saturation ≥96%, were unimpeded in activities of daily living, and were willing to give fully informed consent and adhere to the study protocol. SARS-CoV-2 positivity was defined either as a nasal lateral flow antigen test which became positive within 2 min (STANDARD Q COVID-19 Ag Test, SD Biosensor, Suwon-si, Republic of Korea) or a positive PCR test within the previous 24 hr with a cycle threshold value (Ct) <25 (all viral gene targets), both suggesting high viral loads. The latter was added on November 25, 2021 to include those patients with recent PCR results confirming high viral loads. This was the only change to the pretrial prespecified inclusion/exclusion criteria. Exclusion criteria included taking any potential antivirals or preexisting concomitant medications, chronic illness or significant comorbidity, hematological or biochemical abnormalities, pregnancy (a urinary pregnancy test was performed in females), breastfeeding, or contraindication or known hypersensitivity to any of the study drugs. Randomization and interventions Randomization was performed via a centralized web-app designed by MORU software engineers using RShiny, hosted on a MORU webserver. For all sites, envelopes were generated initially as backup. The no study drug arm comprised a minimum proportion of 20% and uniform randomization ratios were then applied across the treatment arms. For example, for five intervention arms plus the no study drug arm, 20% of patients would be randomized to no study drug and 16% to each of the five interventions. Additional details on the randomization are provided in Appendix 3. All patients received standard symptomatic treatment. Ivermectin (600 μg/kg; 6 mg tablets; Atlantic Laboratories, Thailand) was given once daily for 7 days with food (see Table 1 below). Patients were supplied with a hospital meal of 500–600 kcal containing 20–25% fat. Casirivimab/imdevimab (600 mg/600 mg; Roche, Switzerland) was given once by intravenous infusion following randomization. During this period, other patients were randomized to remdesivir, favipiravir, or fluoxetine (added to the randomization list April 1, 2022). Table 1 Ivermectin dosing table. Daily dose of ivermectin given to patients based on weight. Weight in kgNumber of 6 mg tabletsDose in mgDose in mg/kg40 to <504240.49–0.650 to <605300.51–0.660 to <706360.52–0.670 to <807420.53–0.680 to <908480.54–0.690 to <1009540.55–0.6≥1001060≤0.6 Trial procedures Eligible patients were admitted to the study ward. Baseline investigations included a full clinical examination, rapid SARS-CoV-2 antibody test (BIOSYNEX COVID-19 BSS IgM/IgG, Illkirch-Graffenstaden, France), blood sampling for hematology and biochemistry, an electrocardiogram and a chest radiograph (following local guidance, but this was not a study requirement). After randomization, oropharyngeal swabs (two swabs from each tonsil) were taken as follows. A Thermo Fisher MicroTest flocked swab was rotated against the tonsil through 360o four times and placed in Thermo Fisher M4RT viral transport medium (3 mL). On subsequent days (days 1–7 and then after discharge on day 14), a single swab was taken from each tonsil (left and right, total of 2 swabs). Swabs were transferred separately at 4–8°C, and then frozen at –80°C within 48 hr. Thus, each patient had a total of 20 swabs. The TaqCheck SARS-CoV-2 Fast PCR Assay (Applied Biosystems, Thermo Fisher Scientific, Waltham, MA) was used to quantitate viral load (RNA copies per mL). This assay is a multiplexed real-time PCR method, which detects the SARS-CoV-2 N-gene and S-gene as well as human RNase P in a single reaction. RNase P was used to correct for variation in the sample human cell content. The viral load was quantified against known standards using the ATCC heat-inactivated SARS-CoV-2 VR-1986HK strain 2019-nCoV/USA-WA1/2020. Viral genetic variants were identified using real-time PCR genotyping with the TaqMan SARS-CoV-2 Mutation Panel. Plasma ivermectin concentrations were determined on days 3 and 7 using validated high-performance liquid chromatography linked with tandem mass spectrometry (Tipthara et al., 2021; Kobylinski et al., 2020). Adverse events were graded according to the Common Terminology Criteria for Adverse Events v.5.0 (CTCAE). Adverse event summaries were generated if the adverse event was grade 3 or higher and the adverse event was new, or increased in intensity from study drug administration until the end of the follow-up period. Serious adverse events were recorded separately and reported to the DSMB. Outcome measures, stopping rules, and statistical analysis The primary measure was the rate of viral clearance, expressed as a slope coefficient and presented as a half-life. This was estimated under a Bayesian hierarchical linear model fitted to the daily log10 viral load measurements between days 0 and 7 (18 measurements per patient. Each swab value was treated as independent and identically distributed conditional on the model). Viral loads below the lower limit of quantification (Ct values>40) were treated as left-censored under the model with a known censoring value. The PCRs were done on 96-well plates, each of which included 12 standards of known viral density. The Ct values from the patient swabs were then converted to copies per mL under standard curves estimated using the control data from all available plates (a mixed-effects linear regression model with a random slope and intercept for each plate; each plate therefore has a slightly different left-censoring value). The main model used weakly informative priors (see Appendix 4). The viral clearance rate (i.e., slope coefficient from the model fit) is inversely proportional to the clearance half-life (t1/2=log10 0.5/slope). The treatment effect is defined as the percentage change in the viral clearance rate relative to the contemporaneous no study drug arm (i.e., how much the treatment accelerates viral clearance) (Watson et al., 2022). A 50% increase in viral clearance rate is thus equal to a 33% reduction in the viral clearance half-life. All-cause hospitalization for clinical deterioration (until day 28) was a secondary endpoint. For each studied intervention, the sample size is adaptive. Under the linear model, for each intervention, the treatment effect β is encoded as a multiplicative term on the time since randomization: eβT, where T=1, if the patient was assigned the intervention, and 0 otherwise. Under this specification, β=0 implies no effect (no change in slope), and β>0 implies increase in slope relative to the population mean slope. Stopping rules are then defined with respect to the posterior distribution of β, with futility defined as Prob[β<λ]>0.9; and success defined as Prob[β>λ]>0.9, where λ≥0. Larger values of λ imply smaller sample size to stop for futility but a larger sample size to stop for efficacy. λ was chosen so that it would result in reasonable sample size requirements, as determined previously using a simulation approach based on modeled serial viral load data (Watson et al., 2022). This modelling work suggested that a value of λ=log(1.05) (i.e., 5% increase) would require approximately 50 patients to demonstrate increases in the rate of viral clearance of ~50%, with control of both type 1 and type 2 errors at 10%. The first interim analysis (n=50) was prespecified as unblinded in order to review the methodology and the stopping rules (notably the value of λ). Following this, the stopping threshold was increased from 5% to 12.5% (λ=log(1.125)) because the treatment effect of casirivimab/imdevimab against the SARS-CoV-2 Delta variant was larger than had been expected and the estimated residual error was greater than previously estimated. Thereafter trial investigators were blinded to the virus clearance results. Interim analyses were planned for every batch of additional 25 patients’ PCR data, however, because of delays in setting up the PCR analysis pipeline, the second interim analysis was delayed until April 2022. By that time, data from 145 patients were available (29 patients randomized to ivermectin and 26 patients randomized to no study drug). All analyses were done in a modified intention-to-treat (mITT) population, comprising patients who had >3 days follow-up qPCR data. The safety population includes all patients who received at least one dose of the intervention. A series of linear and nonlinear Bayesian hierarchical models were fitted to the serial viral quantitative PCR (qPCR) data (Appendix 4). For the pharmacokinetic analysis, a previously developed two-compartment disposition model with four transit compartments adjusted for body weight was fitted to the plasma ivermectin levels (Kobylinski et al., 2020). Drug exposures were summarized as the areas under the plasma concentration time curves until 72 hr (AUC0–72) and the maximum peak concentrations (Cmax). This report describes the ivermectin results compared with no treatment, and also includes the unblinded results for the first 10 patients who received casirivimab/imdevimab (recruited until December 16, 2021) to illustrate the pharmacometric method’s sensitivity. All data analysis was done in R version 4.0.2. Model fitting was done in stan via the rstan interface. All code and data are openly accessible via GitHub: https://github.com/jwatowatson/PLATCOV-Ivermectin (Schilling, 2023; copy archived at swh:1:rev:9cd724266ab4f7eab09c5d2a7fd50dac52782957). Results The trial began recruitment on September 30, 2021. On April 18, 2022, ivermectin enrolment was stopped as the prespecified futility margin had been reached. Of the 274 patients screened by then (Figure 1), 224 had been randomized to either ivermectin (46 patients), casirivimab/imdevimab (40 patients; only the unblinded first 10 are reported here), no study drug (45 patients), or other interventions (93 patients: remdesivir, favipiravir, and fluoxetine). This analysis data set therefore comprised 101 patients (46 ivermectin, 10 casirivimab/imdevimab, and 45 no study drug), of whom 5 patients were excluded for either changing treatment before day 2 (n=3), withdrawing from the study (n=1), or because there was no detectable viral RNA at all timepoints (n=1) (Figure 1). In the mITT population (n=96), 60% were female, the median age was 27 (interquartile range [IQR] 25–31) years and the median duration of illness at enrolment was 2 (IQR 2–3) days. Overall, 95% of patients had received at least one dose of a COVID-19 vaccine (Table 2). The median (range) daily ivermectin dose was 550 μg/kg/day (490–600 μg/kg/day). All patients recovered without complications. Virus variants spanned Delta (B.1.617.2), prevalent when the study began, then Omicron BA.1 (B.1.1.529), and then Omicron BA.2 (B.1.1.529) (Figure 1—figure supplement 1). Figure 1 with 1 supplement see all Download asset Open asset Summary of patient characteristics included in the mITT population (n=96). Study CONSORT diagram for the ivermectin analysis. *Prescreening occurred in the hospitals’ Acute Respiratory Infection (ARI) units. Potentially eligible participants (based on age, duration of symptoms, reported comorbidities, and a willingness to consider study participation) were selected by the ARI Nurses to be contacted by the study team. As a result, a high proportion of those assessed for eligibility participated in the study. **SARS CoV-2 Antigen Test Kit (STANDARD Q COVID-19 Ag Test, SD Biosensor, Suwon-si, Republic of Korea). mITT, modified intention-to-treat. Table 2 Summary of patient characteristics included in the mITT population (n=96). Treatment armNumber (total n=96)Age median,years(range)Baseline viral load mean log10 copies per mL(range)Vaccine doses received previously median (range)Antibody positive at baseline from rapid test (%)*Male (%)SitesHTD(n=87)BP(n=5)VJ(n=4)Casirivimab/imdevimab1026.5 (18–31)5.5 (3.7–7.8)2 (0–3)50201000Ivermectin4529(19–45)5.7 (1.9–7.6)2 (0–4)78474122No study drug4127(20–43)5.5 (3–7.7)2 (2–4)90443632 * Defined as IgM or IgG present at enrolment on the rapid antibody test (BIOSYNEX COVID-19 BSS IgM/IgG, Illkirch-Graffenstaden, France) used as per manufacturer’s instructions. HTD: Hospital for Tropical Diseases; BP: Bangplee Hospital; VJ: Vajira Hospital. Virological responses Ninety-six patients in the mITT population had a median of 18 viral load measurements each between days 0 and 7 (range 8–18), of which 7% (121/1700) were below the lower limit of detection. The baseline geometric mean oropharyngeal viral load was 3.6×105 RNA copies/mL (IQR 7.8×104 to 2.8×106) (Figure 2a). Oropharyngeal viral loads declined substantially faster in casirivimab/imdevimab recipients compared to both the ivermectin and no study drug arms (Figure 2b; Figure 3). Under a Bayesian hierarchical linear model, the population mean viral clearance half-life was estimated to be 19.2 hr (95% CI 14.8–23.9 hr) for the no study drug arm. Relative to the no study drug arm, clearance of oropharyngeal virus in patients randomized to ivermectin was 9.1% slower (95% CI –27.2% to +11.8%), whereas with casirivimab/imdevimab it was 52.3% faster (95% CI +7.0% to +115.1%) (Figure 4). This corresponded to prolongation of virus clearance half-life by 1.9 hr (95% CI –2.1 to +6.6) for ivermectin and shortening by 6.5 hr (95% CI –12.0 to –1.1) for casirivimab/imdevimab (Figure 5). In the no study drug arm, there was considerable inter-individual variability in viral clearance; mean estimated half-life values varied from 7 to 42 hr (Figure 5, Figure 5—figure supplement 1). Figure 2 Download asset Open asset Summary of oropharyngeal viral load data in the analysis data set (n=96). (a) Distribution of viral loads at randomization (median of 4 swabs per patient). (b) Individual serial viral load data with x-axis jitter. Median values by study arm are overlaid. The day 14 samples are not used in the primary analysis. Figure 3 Download asset Open asset Predicted ivermectin plasma concentrations over time under the population PK model fit to data from healthy volunteers (Kobylinski et al., 2020), and the ivermectin patients in the PLATCOV study. Mean predicted concentrations with 80% and 95% confidence intervals are shown for daily dosing of 600 μg/kg ivermectin in a 70 kg adult over 1 week for patients (thick line) and healthy volunteers (dashed line). The mean relative bioavailability in patients compared to healthy volunteers was estimated as 2.6. Figure 4 with 3 supplements see all Download asset Open asset Treatment effects mean posterior estimates of the differences in the rate of viral clearance (thick dots) compared to the no study drug arm. 80% (thick lines) and 95% (thin lines) credible intervals under three hierarchical Bayesian models are shown. The gray area shows the futility zone (<12.5% increase in the rate of viral clearance). Results from three models are shown. The main model used to report effect estimates in the text is the linear model (red). Figure 5 with 2 supplements see all Download asset Open asset Individual patient virus clearance half-life estimates over time. The individual oropharyngeal virus clearance half-life mean posterior estimates with 95% credible intervals (lines) are shown (squares/circles/triangles corresponding to the virus genotype: temporarily Delta, Omicron BA.1, Omicron BA.2, respectively). The model estimated mean clearance half-life (95%CI) in untreated patients is shown by the grey line (dashed line-shaded area). Targeted viral genotyping (Appendix 1) indicated that all 10 casirivimab/imdevimab recipients had the SARS CoV-2 Delta variant (B.1.617.1) (Figure 5). The slope and intercept in all models were adjusted for site and virus variant. There were no apparent differences in virus clearance rates across the different virus variants/subvariants; however, relative to the Delta variant, patients with the Omicron BA.2 subvariant had higher baseline viral loads (3.6-fold higher, 95% CI 1.4–9.4), and patients with the Omicron BA.1 subvariant had lower baseline viral loads (0.4-fold lower, 95% CI 0.1–1.1) (Figure 4—figure supplements 1–2). All analytical models of oropharyngeal virus clearance were in excellent agreement, giving near identical point estimates and credible intervals (Figure 4—figure supplement 3). The best fit was the nonlinear model which allows some patients to have viral load increases after randomization (i.e., enrolment before reaching peak viral load), followed by a log-linear decrease. There was no relationship between viral clearance rates and the ivermectin plasma AUC0–72 (p=0.8) or Cmax (p=0.9). Drug exposures were high: all patients had significantly higher plasma concentrations than predicted under the pharmacokinetic model fitted to healthy volunteer data (relative bioavailability 2.6; Figure 3; Kobylinski et al., 2020). Adverse effects The oropharyngeal swabbing and all treatments were well-tolerated. The three serious adverse events were all in the no study drug arm (see Supplementary file 1; Supplementary file 2). Two patients had raised creatinine phosphokinase (CPK) levels (>10 times ULN) attributed to COVID-19-related skeletal muscle damage. This improved with fluids and supportive management. The third patient was readmitted 1 day after discharge because of chest pain and lethargy. All investigations were normal and the patient was discharged the following day. Six patients reported transient visual disturbance after taking ivermectin (although not classified as grade 3 or above). Three of these withdrew from the treatment (Appendix 2). All visual symptoms resolved quickly after the drug was stopped. Ophthalmology review confirmed that no visual abnormality remained. Discussion These first data from the PLATCOV adaptive platform study show that ivermectin does not have a measurable antiviral effect in early symptomatic COVID-19 under our study methodology. In contrast, the preliminary results with casirivimab/imdevimab in patients infected with the SARS-CoV-2 Delta variant showed an approximate 50% acceleration in the viral clearance rate. This confirmed that the study methodology identifies efficiently those treatments which have clinically relevant antiviral effects in vivo. It remains uncertain whether any of the proposed, and often recommended, repurposed potential antiviral treatments have significant in vivo antiviral activity in COVID-19. This continued uncertainty, after 3 years of the pandemic, highlights the limitations of the tools currently used to assess antiviral activity in vivo. Clinically effective monoclonal antibodies and specific antiviral drugs have been developed. It is increasingly accepted that they are most effective early in the course of COVID-19 infection (O’Brien et al., 2021; Jayk Bernal et al., 2022; Hammond et al., 2022; Gottlieb et al., 2022) (whereas anti-inflammatory agents have life-saving benefit later in the disease process when severe pneumonitis has developed). Unfortunately, these efficacious antiviral medicines are not generally available outside high-income settings. Meanwhile repurposed therapeutics, which offered the prospect of affordable and generally available medicines, have been selected for clinical use based on in vitro activity in cell cultures, sometimes on animal studies, or based upon clinical trials which often had subjective or infrequent endpoints, or were conducted in late-stage infections in hospitalized patients. The majority of these trials have been underpowered. In a review of 1314 registered COVID-19 studies, of which 1043 (79%) were randomized controlled trials, the median (IQR) sample size was 140 patients (70–383) (McLean et al., 2023). These uncertainties have created confusion and, for ivermectin, strongly polarized views. The method of assessing antiviral activity in early COVID-19 reported here builds on extensive experience of antiviral pharmacodynamic assessments in other viral infections. It has the advantage of simplicity. It also avoids many of the limitations of unvalidated in vivo animal models (Muñoz-Fontela et al., 2022). Only a relatively small number of patients are needed to identify antiviral activity in vivo (Watson et al., 2022). In this trial, with only 41 controls and 45 subjects receiving ivermectin, acceleration in viral clearance of more than 12.5% could be excluded with high certainty. Smaller numbers are required to show efficacy. These sample sizes are an order of magnitude smaller than required for the more commonly used endpoint of time to viral clearance (PCR negativity) (Watson et al., 2022). In addition, the procedures are well-tolerated: daily oropharyngeal swabbing is much more acceptable than frequent nasopharyngeal sampling. Oropharyngeal viral loads have been shown to be both more and less sensitive for the detection of SARS-CoV-2 infection. Although rates of viral clearance are very likely to be similar from the two body sites, this should be established for comparison with other studies. Using less frequent nasopharyngeal sampling in larger numbers of patients, clinical trials of monoclonal antibodies, molnupiravir, and ritonavir-boosted nirmatrelvir, have each shown that accelerated viral clearance is associated with improved clinical outcomes (Weinreich et al., 2021; Jayk Bernal et al., 2022; Hammond et al., 2022). These data suggest that reduction in viral load could be used as a surrogate of clinical outcome in COVID-19. In contrast, the PINETREE study, which showed that remdesivir significantly reduced disease progression in COVID-19, did not find an association between viral clearance and therapeutic benefit. This seemed to refute the usefulness of viral clearance rates as a surrogate for rates of clinical recovery. However, the infrequent sampling in all these studies substantially reduced the precision of the viral clearance estimates (and thus increased the risk of type 2 errors). Using the frequent sampling employed in the PLATCOV study, we have shown recently that remdesivir does accelerate SARS-CoV-2 viral clearance (Jittamala et al., 2023), as would be expected from an efficacious antiviral drug. This is consistent with therapeutic responses in other viral infections (Natori et al., 2018; Mellors et al., 1997). Taken together, the weight of evidence suggests that accelerated viral clearance does reflect therapeutic efficacy in early COVID-19," @default.
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• W4323320726 title "Author response: Pharmacometrics of high-dose ivermectin in early COVID-19 from an open label, randomized, controlled adaptive platform trial (PLATCOV)" @default.
• W4323320726 doi "https://doi.org/10.7554/elife.83201.sa2" @default.
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