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Letter to the Editor| Volume 16, ISSUE 5, P757-758, September 2022

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Monkeypox is a global public health emergency: The role of repurposing cholesterol lowering drugs not to be forgotten

Published:August 19, 2022DOI:https://doi.org/10.1016/j.jacl.2022.08.003
Monkeypox is a global public health emergency: The role of repurposing cholesterol lowering drugs not to be forgotten
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      Keywords

      On July 23, 2022, World Health Organization (WHO) declared the current monkeypox outbreak a Public Health Emergency of International Concern (PHEIC).
      • Nuzzo JB
      • Borio LL
      The WHO declaration of monkeypox as a global public health emergency.
      JAMA. 2022; (Published online July 27)https://doi.org/10.1001/jama.2022.12513
      Less than a week later New York and San Francisco declared a state of emergency due to an alarming rise in the number of monkeypox cases.

      New York State. 8-29-2022. Declaring a disaster in the State of New York. governor.ny.gov/executive-order/no-20-declaring-disaster-state-new-york

      ,

      City and County of San Francisco. 8-28-2022. Office of the Mayor. San Francisco to declare local public health emergency for monkeypox. sfmayor.org/article/san-francisco-declare-local-public-health-emergency-monkeypox

      By July 29, 2022; 22, 141 cases of monkeypox had been reported globally in the countries that have not been reported this disease historically.

      Centers for Disease Control and Prevention. 8-29-2022. Monkeypox outbreak global map. cdc.gov/poxvirus/monkeypox/response/2022/world-map.html

      Of these cases 4,906 were reported from the USA.
      As a preventive measure effective smallpox vaccination is currently offered in many countries as Pre-Exposure Prophylaxis for risk groups to prevent monkeypox but it is not widely available and vaccination programs have only just been initiated.

      Centers for Disease Control and Prevention. 8-28-2022. Considerations for monkeypox vaccination. cdc.gov/poxvirus/monkeypox/considerations-for-monkeypox-vaccination.html

      Thus, the number of monkeypox patient cases will continue to rise. There are several antiviral medications including cidofovir, brincidofovir, and tecovirimat to treat monkeypox.
      • Siegrist EA
      • Sassine J.
      Antivirals with activity against monkeypox: a clinically oriented review.
      Clin Infect Dis. 2022; : ciac622https://doi.org/10.1093/cid/ciac622
      Of these, the most effective medication against monkeypox is tecovirimat which inhibits the function of a major envelope protein required for the production of extracellular virus. Tecovirimat thus prevents the mature virus from leaving an infected cell. The recommended duration of tecovirimat treatment is 14 days.
      • Siegrist EA
      • Sassine J.
      Antivirals with activity against monkeypox: a clinically oriented review.
      Clin Infect Dis. 2022; : ciac622https://doi.org/10.1093/cid/ciac622
      Currently there is very little data of the effectiveness of tecovirimat treatment against monkeypox although several clinical trials are ongoing.
      • Siegrist EA
      • Sassine J.
      Antivirals with activity against monkeypox: a clinically oriented review.
      Clin Infect Dis. 2022; : ciac622https://doi.org/10.1093/cid/ciac622
      ,
      • Adler H
      • Gould S
      • Hine P
      • et al.
      Clinical features and management of human monkeypox: a retrospective observational study in the UK.
      Lancet Infect Dis. 2022; 22 (Erratum in: Lancet Infect Dis. 2022 Jul;22(7):e177. Erratum in: Lancet Infect Dis. 2022 Jul;22(7):e177): 1153-1162https://doi.org/10.1016/S1473-3099(22)00228-6
      It can be expected that clinical trials regarding effectiveness of tecovirimat will last very long. So, at the current situation repurposing of cholesterol lowering drugs as adjuvants to tecovirimat, including statins, PCSK9 inhibitors and fenofibrates is an attractive strategy and has already been applied in the COVID-19 pandemic.
      • Vuorio A
      • Kovanen PT.
      Statins as adjuvant therapy for COVID-19 to calm the stormy immunothrombosis and beyond.
      Front Pharmacol. 2021; 11579548https://doi.org/10.3389/fphar.2020.579548
      , 
      • Vuorio A
      • Kovanen PT.
      PCSK9 inhibitors for COVID-19: an opportunity to enhance the antiviral action of interferon in patients with hypercholesterolaemia.
      J Intern Med. 2021; 289: 749-751https://doi.org/10.1111/joim.13210
      , 
      • Vuorio A
      • Brinck J
      • Kovanen PT.
      Continuation of fibrate therapy in patients with metabolic syndrome and COVID-19: a beneficial regime worth pursuing.
      Ann Med. 2022; 54: 1952-1955https://doi.org/10.1080/07853890.2022.2095667
      The interest to repurposing cholesterol lowering drugs, particularly statins, is best known among COVID-19 patients.
      • Talasaz AH
      • Sadeghipour P
      • Aghakouchakzadeh M
      • et al.
      Investigating lipid-modulating agents for prevention or treatment of COVID-19: JACC state-of-the-art review.
      J Am Coll Cardiol. 2021; 78: 1635-1654https://doi.org/10.1016/j.jacc.2021.08.021
      Moreover, there are several examples of this repurposing strategy regarding other severe infections. Statins have been repurposed in the treatment of influenza and Ebola.
      • Fedson DS.
      Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola.
      Ann Transl Med. 2016; 4: 421https://doi.org/10.21037/atm.2016.11.03
      With Ebola infection, statins may result in the production of fusion-inefficient Ebola virus particles.
      • Lee J
      • Kreutzberger AJB
      • Odongo L
      • et al.
      Ebola virus glycoprotein interacts with cholesterol to enhance membrane fusion and cell entry.
      Nat Struct Mol Biol. 2021; 28: 181-189https://doi.org/10.1038/s41594-020-00548-4
      PCSK9 inhibitors have been used to treat Dengue virus infection because PCSK9 inhibitors enhance secretion of type I interferons.
      • Gan ES
      • Tan HC
      • Le DHT
      • et al.
      Dengue virus induces PCSK9 expression to alter antiviral responses and diseases outcomes.
      J Clin Invest. 2020; 130: 5223-5234https://doi.org/10.1172/JCI137536
      Fenofibrate has been shown to decrease mortality and morbidity among Japanese encephalitis patients.
      • Sehgal N
      • Kumawat KL
      • Basu A
      • Ravindranath V.
      Fenofibrate reduces mortality and precludes neurological deficits in survivors in murine model of Japanese encephalitis viral infection.
      PLoS One. 2012; 7: e35427https://doi.org/10.1371/journal.pone.0035427
      Compared to Japanese encephalitis vaccination Sehkal and coauthors mention the potential usefulness of fenofibrate especially when treating endemic infections.
      • Sehgal N
      • Kumawat KL
      • Basu A
      • Ravindranath V.
      Fenofibrate reduces mortality and precludes neurological deficits in survivors in murine model of Japanese encephalitis viral infection.
      PLoS One. 2012; 7: e35427https://doi.org/10.1371/journal.pone.0035427
      While currently there is clearly a lack of studies repurposing cholesterol lowering drugs for the treatment of Monkeypox more attention needs to be given how such viral infections effect the re-distribution of cellular cholesterol.
      • Glitscher M
      • Hildt E.
      Endosomal cholesterol in viral infections - a common denominator?.
      Front Physiol. 2021; 12750544https://doi.org/10.3389/fphys.2021.750544
      For example, the efficient endosomal re-distribution of cholesterol is essential for viral life cycles. If this cholesterol re-distribution can be disrupted the viral life cycles may be inhibited or even collapse.
      • Glitscher M
      • Hildt E.
      Endosomal cholesterol in viral infections - a common denominator?.
      Front Physiol. 2021; 12750544https://doi.org/10.3389/fphys.2021.750544
      Fenofibrate also seems to have this ability, at least in vitro.
      • Glitscher M.
      • Martín DH
      • Woytinek K
      • et al.
      Targeting cholesterol metabolism as efficient antiviral strategy against the hepatitis E virus.
      Cell Mol Gastroenterol Hepatol. 2021; 12: 159-180https://doi.org/10.1016/j.jcmgh.2021.02.002
      Taken together, monkeypox appears to become yet another global public health problem, and, as such, it is a reminiscent of the current COVID-19 pandemic and its predecessors. Therefore, the potential beneficial role of repurposing cholesterol lowering drugs should not be forgotten in this newly emerging viral outbreak. Patients with severe hypercholesterolemia should not stop taking cholesterol-lowering medication after contracting Monkeypox. If tecovirimat medication is started for Monkeypox, simvastatin should be changed to another statin, analogously when treating SARS-CoV-2 infection with Paxlovid.
      • Vuorio A
      • Kovanen PT
      • Raal F.
      Cholesterol-lowering drugs for high-risk hypercholesterolemia patients with COVID-19 while on Paxlovid™ therapy.
      Future Virol. 2022; (Ahead of print 2)https://doi.org/10.2217/fvl-2022-0060

      Declaration of Competing Interest

      AV has received consultancy fees Amgen and Novartis. PTK has received consultancy fees, lecture honoraria, and/or travel fees from Amgen, Novartis, Raisio Group, and Sanofi. FR has received research grants, honoraria, or consulting fees for professional input and/or lectures from Sanofi, Regeneron, Amgen, and Novartis.

      References

        • Nuzzo JB
        • Borio LL
        The WHO declaration of monkeypox as a global public health emergency.
        JAMA. 2022; (Published online July 27)https://doi.org/10.1001/jama.2022.12513
        View in Article

      2. New York State. 8-29-2022. Declaring a disaster in the State of New York. governor.ny.gov/executive-order/no-20-declaring-disaster-state-new-york

        View in Article

      3. City and County of San Francisco. 8-28-2022. Office of the Mayor. San Francisco to declare local public health emergency for monkeypox. sfmayor.org/article/san-francisco-declare-local-public-health-emergency-monkeypox

        View in Article

      4. Centers for Disease Control and Prevention. 8-29-2022. Monkeypox outbreak global map. cdc.gov/poxvirus/monkeypox/response/2022/world-map.html

        View in Article

      5. Centers for Disease Control and Prevention. 8-28-2022. Considerations for monkeypox vaccination. cdc.gov/poxvirus/monkeypox/considerations-for-monkeypox-vaccination.html

        View in Article
        • Siegrist EA
        • Sassine J.
        Antivirals with activity against monkeypox: a clinically oriented review.
        Clin Infect Dis. 2022; : ciac622https://doi.org/10.1093/cid/ciac622
        View in Article
        • Adler H
        • Gould S
        • Hine P
        • et al.
        Clinical features and management of human monkeypox: a retrospective observational study in the UK.
        Lancet Infect Dis. 2022; 22 (Erratum in: Lancet Infect Dis. 2022 Jul;22(7):e177. Erratum in: Lancet Infect Dis. 2022 Jul;22(7):e177): 1153-1162https://doi.org/10.1016/S1473-3099(22)00228-6
        View in Article
        • Vuorio A
        • Kovanen PT.
        Statins as adjuvant therapy for COVID-19 to calm the stormy immunothrombosis and beyond.
        Front Pharmacol. 2021; 11579548https://doi.org/10.3389/fphar.2020.579548
        View in Article
        • Vuorio A
        • Kovanen PT.
        PCSK9 inhibitors for COVID-19: an opportunity to enhance the antiviral action of interferon in patients with hypercholesterolaemia.
        J Intern Med. 2021; 289: 749-751https://doi.org/10.1111/joim.13210
        View in Article
        • Vuorio A
        • Brinck J
        • Kovanen PT.
        Continuation of fibrate therapy in patients with metabolic syndrome and COVID-19: a beneficial regime worth pursuing.
        Ann Med. 2022; 54: 1952-1955https://doi.org/10.1080/07853890.2022.2095667
        View in Article
        • Talasaz AH
        • Sadeghipour P
        • Aghakouchakzadeh M
        • et al.
        Investigating lipid-modulating agents for prevention or treatment of COVID-19: JACC state-of-the-art review.
        J Am Coll Cardiol. 2021; 78: 1635-1654https://doi.org/10.1016/j.jacc.2021.08.021
        View in Article
        • Fedson DS.
        Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola.
        Ann Transl Med. 2016; 4: 421https://doi.org/10.21037/atm.2016.11.03
        View in Article
        • Lee J
        • Kreutzberger AJB
        • Odongo L
        • et al.
        Ebola virus glycoprotein interacts with cholesterol to enhance membrane fusion and cell entry.
        Nat Struct Mol Biol. 2021; 28: 181-189https://doi.org/10.1038/s41594-020-00548-4
        View in Article
        • Gan ES
        • Tan HC
        • Le DHT
        • et al.
        Dengue virus induces PCSK9 expression to alter antiviral responses and diseases outcomes.
        J Clin Invest. 2020; 130: 5223-5234https://doi.org/10.1172/JCI137536
        View in Article
        • Sehgal N
        • Kumawat KL
        • Basu A
        • Ravindranath V.
        Fenofibrate reduces mortality and precludes neurological deficits in survivors in murine model of Japanese encephalitis viral infection.
        PLoS One. 2012; 7: e35427https://doi.org/10.1371/journal.pone.0035427
        View in Article
        • Glitscher M
        • Hildt E.
        Endosomal cholesterol in viral infections - a common denominator?.
        Front Physiol. 2021; 12750544https://doi.org/10.3389/fphys.2021.750544
        View in Article
        • Glitscher M.
        • Martín DH
        • Woytinek K
        • et al.
        Targeting cholesterol metabolism as efficient antiviral strategy against the hepatitis E virus.
        Cell Mol Gastroenterol Hepatol. 2021; 12: 159-180https://doi.org/10.1016/j.jcmgh.2021.02.002
        View in Article
        • Vuorio A
        • Kovanen PT
        • Raal F.
        Cholesterol-lowering drugs for high-risk hypercholesterolemia patients with COVID-19 while on Paxlovid™ therapy.
        Future Virol. 2022; (Ahead of print 2)https://doi.org/10.2217/fvl-2022-0060
        View in Article

      Article info

      Publication history

      Published online: August 19, 2022
      Accepted: August 16, 2022
      Received: August 4, 2022

      Identification

      DOI: https://doi.org/10.1016/j.jacl.2022.08.003

      Copyright

      © 2022 National Lipid Association. Published by Elsevier Inc. All rights reserved.

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