Clinical Trial of Efficacy and Toxicity of Disoproxil Tenofovir Fumarate and Emtricitabine for Mild to Moderate SARS-CoV-2 Infections

  1. E.A.G. Arruda
  2. R.J. Pires-Neto
  3. M.S. Medeiros
  4. J. Quirino-Filho
  5. M. Clementino
  6. R.N.D.G. Gondim
  7. L.M.V.C. Magalhães
  8. K.F. Cavalcante
  9. V.A.F. Viana
  10. Liana Perdigão Mello
  11. R.B Martins
  12. A.A. Santos
  13. P.J.C. Magalhães
  14. A. Havt
  15. N.P. Lopes
  16. E. Arruda-Neto
  17. A.A.M. Lima
  18. study group members

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Abstract

This study aimed to evaluate the efficacy and toxicity of tenofovir (TDF) and TDF combined with emtricitabine (TDF/FTC) in patients with mild to moderate COVID-19 infections. We conducted a randomized, double-blind, placebo-controlled clinical trial in patients with clinical suspicion of mild to moderate respiratory infection caused by SARS-CoV-2 who were treated at an outpatient clinic. Patients were randomly recruited to take 10 days of TDF (300 mg/day), TDF (300 mg/day) combined with FTC (200 mg/day) or placebo Vitamin C (500 mg/day). The primary parameter was the score of symptoms and predictive signs of COVID-19, assessed on the seventh day of patient follow-up. From a total of 309 patients with clinical suspicion of SARS-CoV-2, 227 met the inclusion criteria and were randomly distributed into the following groups: (a) 75 (one did not initiate treatment) in the TDF group; (b) 74 in the TDF combined with FTC group; and (c) 77 in the Vitamin C group (placebo). Of the 226 patients, 139 (62%) were positive for SARS-CoV-2. Fever (≥37.8°C), ageusia or dysgeusia, anosmia or dysosmia, and two or more clinical symptoms or signs were significantly associated with SARS-CoV-2 infection. There was no significant change in clinical score based on clinical symptoms and signs between treatment groups. Patients with mild to moderate infection by SARS-CoV-2 had higher concentrations of G-CSF, IL-1β, IL-6 and TNF-α compared to patients without infection. Patients with mild to moderate respiratory infection, with fever (≥37.8°C), loss of smell, loss of taste and two or more symptoms, have a better prediction for the diagnosis of COVID-19. Patients with SARS-CoV-2 showed higher and more persistent proinflammatory cytokines profile compared to patients not infected with SARS-CoV-2. Pharmacological intervention with TDF or TDF combined with FTC did not change the clinical signs and symptoms score in mild to moderate respiratory infection in patients with SARS-CoV-2 compared to the Vitamin C group (placebo).

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  1. ScreenIT

    SciScore for 10.1101/2021.09.28.21264242: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: After signing the consent form, patients with mild to moderate respiratory infection and clinical suspicion of COVID-19 were invited to participate in the study.
    IRB: The SAEs were registered in a specific form, and they were reported within 14 days to the Study Management Group to the Research Ethics Committee (COMEPE).
    Sex as a biological variableSelection and recruitment of participants: We selected adult patients aged 18-60 years and of both genders, who met the following inclusion criteria: (a) age between 18-60 years; and (b) clinical suspicion of mild to moderate COVID-19 respiratory infection.
    RandomizationStudy design, site, and population: The study design was a prospective, clinical trial, randomized, double-blind, placebo-controlled.
    Blindingnot detected.
    Power AnalysisSample size and statistical analysis: The estimated sample size was calculated at 73 patients for each intervention group (Total = 219 patients) to achieve statistical power of 80% (1 – Beta; type-II error) and statistical significance of p = 0.05 (Alpha: type-I error) to reduce the clinical duration of the disease in the groups receiving the drugs by 20% compared to the clinical duration of the disease in the Vitamin C placebo control group, with 15% losses by exit from the study.

    Table 2: Resources

    Antibodies
    SentencesResources
    Biomarkers in the immune-inflammatory response: IgM and IgG tests were performed with the LIAISON® SARS-CoV-2 S1/S2 IgG and IgM kit (DiaSorin, Saluggia, Italy) a chemiluminescence-based immunoassay for the quantitative determination of antibodies SARS-CoV-2 anti-S1 and anti-S2 IgG and qualitative IgM antibodies to SARS-CoV-2 in human serum or plasma samples, following the manufacturer’s protocol.
    anti-S1
    suggested: None
    anti-S2 IgG
    suggested: None
    qualitative IgM
    suggested: None
    Software and Algorithms
    SentencesResources
    All data were de-identified and statistical analysis was done using SPSS Statistics 20.0 (IBMCorporation, https://www.ibm.com).
    SPSS
    suggested: (SPSS, RRID:SCR_002865)
    We used GraphPad Prism version 3.0 for Windows (GraphPad Software, https://www.graphpad.com) and ArcGIS software version 9.0
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    ArcGIS
    suggested: (ArcGIS for Desktop Basic, RRID:SCR_011081)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The use of viral load and signs and symptoms scores on the seventh day of illness were a limitation of the present study. As noted, the viral load is practically zero on the seventh day of illness in all experimental groups, which makes it difficult to evaluate the drugs in their antiviral action. As the selected COVID-19 cases had mild to moderate disease, it is likely that the majority had already recovered regardless of the drugs. Considering that most patients included in the study made adequate use of the drugs, judging by the control of their intake, we might have observed differences if we had followed symptoms and signs and viral load earlier, before the seventh day of illness. Summary of conclusions: The presence of fever (≥37.8°C), anosmia or dysosmia, ageusia or dysgeusia, with two or more symptoms in patients with mild to moderate respiratory infection, indicate the diagnosis of COVID-19. The score based on these symptoms and signs was useful for use in the clinical trial and for the implementation of preventive measures in the transmission of COVID-19. Univariate and multivariate logistic regression analysis for the predictive parameters of symptoms and signs associated with mild to moderate COVID-19 showed that anosmia or dysosmia symptoms, in the absence of sore throat, have accuracy and high sensitivity to predict COVID-19, compared to mild and moderate respiratory infections due to causes other than SARS-CoV-2. Pharmacological intervention with TDF and TDF / ...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04712357RecruitingClinical Experimentation With Tenofovir Disoproxyl Fumarate …

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.09.28.21264242v1 on medRxiv