Tenofovir Disoproxil Fumarate and severity of COVID-19 in people with HIV infection

  1. J Del Amo
  2. R Polo
  3. S Moreno
  4. E Martínez
  5. A Cabello
  6. JA Iribarren
  7. A Curran
  8. J Macías
  9. M Montero
  10. C Dueñas
  11. AI Mariño
  12. S Pérez de la Cámara
  13. A Díaz
  14. JR Arribas
  15. I Jarrín
  16. MA Hernán

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Abstract

Background

Effective, safe, and affordable antivirals are needed for COVID-19. Tenofovir has not been studied in randomized trials despite evidence consistent with its effectiveness against COVID-19.

Methods

We studied HIV-positive individuals on antiretroviral therapy (ART) in 2020 at 69 HIV clinics in Spain. We collected data on sociodemographics, ART, CD4-cell count, HIV-RNA viral load, comorbidities and the following outcomes: laboratory-confirmed SARS-CoV-2 infection, COVID-19 hospitalization, intensive care unit (ICU) admission and death. We compared the 48-week risks for individuals receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), tenofovir alafenamide (TAF)/ FTC, abacavir (ABC)/lamivudine (3TC), and other regimes. All estimates were adjusted for clinical and sociodemographic characteristics via inverse probability weighting.

Results

Of 51,558 eligible individuals, 39.6% were on TAF/FTC, 11.9% on TDF/FTC, 26.6% on ABC/3TC, 21.8% on other regimes. There were 2,402 documented SARS-CoV-2 infections (425 hospitalizations, 45 ICU admissions, 37 deaths). Compared with TAF/FTC, the estimated risk ratios (RR) (95% CI) of hospitalization were 0.66 (0.43, 0.91) for TDF/FTC and 1.29 (1.02, 1.58) for ABC/3TC, the RRs of ICU admission were 0.28 (0.11, 0.90) for TDF/FTC and 1.39 (0.70, 2.80) for ABC/3TC, and the RRs of death were 0.37 (0.23, 1.90) for TDF/FTC and 2.02 (0.88-6.12) for ABC/3TC. The corresponding RRs of hospitalization for TDF/FTC were 0.49 (0.24, 0.81) in individuals ≥50 years and 1.15 (0.59, 1.93) in younger individuals.

Conclusion

Our findings suggest that, compared with other antiretrovirals, TDF/FTC lowers COVID-19 severity among HIV-positive individuals with virological control. This protective effect may be restricted to individuals aged 50 years and older.

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    SciScore for 10.1101/2021.11.11.21266189: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: This study was approved by the institutional review board at University Hospital Ramón y Cajal, Madrid, Spain.
    Sex as a biological variableTo estimate the denominator of the weights we fit a multinomial logistic model for the four NRTI combinations with covariates: age (in years, linear and quadratic terms), sex (male, female), transmission category (heterosexual, homo/bisexual, injecting drug use, other), country of origin (Spain, other), CD4 (<350, 350-500, >500 cells/mm3), and indicators for hypertension, diabetes, chronic renal disease, cardiovascular disease, and treatment with immunosuppressants or corticosteroids.
    RandomizationThe goal was to emulate a (hypothetical) target trial in which individuals are randomly assigned to a particular nucleos(t)ide reverse transcriptase inhibitor (NRTI) combination before the start of SARS-CoV-2 transmission in their communities.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All analyses were conducted with Stata, version 15.0 (StataCorp).
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    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:
    Our study has some limitations. First, residual confounding by yet to be identified factors cannot be excluded. However, such residual confounding seems unlikely because we adjusted for known factors that affect both antiretroviral treatment choice and COVID-19 severity. Therefore, the lowest risk of hospitalization in those receiving TDF/FTC cannot be easily explained by residual confounding. Second, we could not collect SARS-CoV-2 testing frequency for all individuals. Testing patterns, however, are expected to affect the detection of mild (and asymptomatic) disease but not that of more severe outcomes like hospitalization, ICU admissions, and death. Third, missing data on comorbidities led to the exclusion of 22% of otherwise eligible individuals. However, estimates did not materially change in unadjusted analyses that included individuals with missing data on comorbidities. Fourth, even a large cohort like this one cannot provide precise estimates for the risks of infrequent events such as ICU admissions and deaths. In summary, our findings suggest that treatment with TDF/FTC results in a lower severity of COVID-19 than treatment with other antiretrovirals among HIV-positive individuals with adequate virological control. This protective effect may be largely restricted to individuals aged 50 years and older. Confirmatory randomized trials of TDF/FTC for the prophylaxis and early treatment of COVID-19 are warranted.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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

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  2. Version published to 10.1101/2021.11.11.21266189v1 on medRxiv