key: cord-0703375-z4eof8jo
authors: Lee, K.; Heberer, K.; Gao, A.; Becker, D. J.; Loeb, S.; Makarov, D.; Gulanski, B.; Duvall, S.; Aslan, M.; Lee, J.; Hauger, R.; Shih, M.-C.; Lynch, J.; Rettig, M.
title: A population-level analysis of the protective effects of androgen deprivation therapy against COVID-19 disease incidence and severity
date: 2021-05-10
journal: nan
DOI: 10.1101/2021.05.10.21255146
sha: ae06407c03ad1e0aaadf3c6255f1cd92243947a9
doc_id: 703375
cord_uid: z4eof8jo

ABSTRACT Importance: The incidence and severity of coronavirus disease 19 (COVID-19) is higher in men. Sex hormones potentially offer one explanation for differences by sex. Objective: To determine whether men exposed to androgen deprivation therapy (ADT) have lower incidence and severity of COVID-19. Design: We conducted an observational study of male Veterans treated in the Veterans Health Administration from February 15th to July 15th, 2020. We developed a propensity score model to predict the likelihood to undergo Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing. We performed multivariable logistic regression modeling adjusted with inverse probability weighting to examine the relationship between ADT and COVID-19 incidence. We conducted logistic regression analysis among COVID-19 patients to test the association between ADT and COVID-19 severity. Setting: The U.S. Department of Veterans Affairs Participants: The study sample consisted of 6,250,417 male Veterans who were alive as of February 15, 2020. Exposure: Exposure to ADT was defined as having any prescription for a luteinizing hormone releasing hormone analogue or an antiandrogen in the six months prior to the index date. Main Outcomes and Measures: To assess incidence, we used a binary variable indicating any positive reverse transcriptase polymerase chain reaction SARS-CoV-2 test result through July 15, 2020. To measure severity, we constructed a binary variable indicating whether a patient was admitted to the intensive care unit, placed on mechanical ventilation, or dead in the 60 days following a positive test up to July 15, 2020. Results: We identified 246,087 patients who had been tested for SARS-CoV-2, of whom 3,057 were exposed to ADT, and 36,096 patients with cancer and no ADT exposure. Of these, 295 ADT patients and 2,427 other cancer patients had COVID-19 illness. In the primary, propensity-weighted comparison of ADT patients to cancer patients not on ADT, ADT was associated with decreased likelihood of testing positive for SARS-CoV-2 (adjusted OR, 0.88 [95% CI, 0.81-0.95]; p=0.001). ADT was associated with fewer severe COVID-19 outcomes (OR 0.72 [95% CI 0.53-0.96]; p=0.03). Conclusions and Relevance: ADT is associated with reduced incidence and severity of COVID-19 amongst male Veterans. Repurposing of drugs that modulate androgen production and/or action may represent viable potential treatments for COVID-19.

coronavirus disease 2019 have rapidly disseminated across the globe and caused 96 more than one million deaths. 1 The incidence and severity of COVID-19 have been related to 97 multiple factors, including age, comorbid conditions, immunosuppression, smoking, race, and 98 sex. 2-4 Whereas men and women manifest a similar incidence of COVID-19, male sex is a risk 99 factor for more severe illness. The severity of COVID-19 as indicated by admission to an 100 intensive care unit (ICU), requirement for mechanical ventilation, or mortality is approximately 101 two-fold higher in men. 5, 6 This sex disparity has been observed in Asia, North America, Europe, 102 and across individual countries on each of the continents.

smoking history), incidence of comorbidities such as lung and heart disease, and biology, 105 including variations in sex hormones. Specifically, androgens including testosterone and 106 dihydrotestosterone may worsen COVID-19 severity through two non-mutually exclusive 107 physiologic effects. First, androgens are known to suppress both innate and adaptive immunity, 108 which may increase susceptibility to the SARS-CoV-2 virus and disease severity. 7,8 Second, morbidity and mortality. 14,15 TMPRSS2 gene variants has also been found to confer a two-fold 120 increase in H1N1 influenza severity supporting the hypothesis that androgen regulation of 121 

The study sample consisted of all male Veterans who were alive as of February 15, 144 2020. The earliest testing date reported in the CSDR is February 16, 2020. Therefore, we 145 considered anyone alive as of February 15, 2020 as having been eligible to be tested for SARSpatients who underwent SARS-CoV-2 testing matched to patients who did not undergo SARSpatients who tested positive for SARS-CoV-2 to investigate ADT use and COVID-19 severity.

The index date for the incidence analysis and the severity analysis was February 15, 2020 and 152 the date of first positive SARS-CoV-2 test result, respectively.

Exposure 154 Exposure to androgen deprivation therapy (ADT) was defined as having any prescription 155 for a luteinizing hormone releasing hormone analogue (LHRH) (buserelin, degarelix, goserelin, 156 historelin, leuprolide, or triptorelin) or an antiandrogen (abiraterone, apalutamide, bicalutamide, it is highly unlikely to be prescribed antiandrogens as a monotherapy. 185 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 10, 2021. ; https://doi.org/10.1101/2021.05.10.21255146 doi: medRxiv preprint

In our analysis of male U.S. Veterans tested for SARS-CoV-2, ADT use was associated 241 with a reduced incidence and severity of COVID-19 compared to Veterans with non-prostate other comorbidities, and race) and the likelihood for undergoing SARS-CoV-2 testing. A reduced 245 incidence of COVID-19 was also observed among ADT patients compared to all SARS-CoV-2-246 tested Veterans not on ADT as well as Veterans with prostate cancer not on ADT.

The effects of ADT on the incidence of COVID-19 has been reported by two groups. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 10, 2021. ; https://doi.org/10.1101/2021.05.10.21255146 doi: medRxiv preprint outcomes, but the authors recognized that robust statistics were not feasible due to limited sample size, despite being significantly larger than the Italian cohort. 18 Based on a small cohort Ongoing work in VA may provide further clarify the association between ADT and 292 COVID-19 illness and determine the utility of ADT agents including LHRH analogs, androgen FDA-approved LHRH analog that rapidly suppresses serum testosterone concentrations. A 

There is a paucity of effective treatments for severe COVID-19. In the Solidarity trial,

Our analysis of Veterans enrolled in the VHA suggests an association of ADT exposure 316 with reduced incidence and severity of COVID-19. Repurposing of drugs that modulate 317 androgen production and/or action may represent viable potential treatments for COVID-19.

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

The World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard. variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population 358 cohorts from multiple continents

Gene of the month: TMPRSS2 (transmembrane serine 361 protease 2)

Identification of TMPRSS2 as a Susceptibility Gene for 363 Severe 2009 Pandemic A(H1N1) Influenza and A(H7N9) Influenza

A Randomized Trial of Convalescent