What existing drugs are currently being evaluated or repurposed for treatment of Coronavirus (Covid-19) infection?

There are currently no drugs specifically approved for treatment of Covid-19 infections. However, there are legions of therapies that are being considered, tried, and/or evaluated in clinical trials. Many experts believe a combination of drugs may be necessary for optimal therapy. Here is my select list of potentially promising drugs from gleaning the literature and online resources to date.1-16

  • Remdisivir: A broad spectrum investigational nucleoside analogue, originally developed to treat a variety of viruses, including Ebola, SARS and MERS. Active in vitro against Covid-19. Favorable results have been reported in some cases, including the first reported patient in the U.S.
  • Chloroquine: An old drug used for its antimalarial activity as well as for its immune modulation and anti-inflammatory properties. Has also been found to be active in mice against a variety of viruses, including certain enteroviruses, Zika virus, influenza A H5N1.  Active in vitro against Covid-19, though hydroxychloroquine may be more effective. Evidence for its efficacy in treating acute viral infections in humans is currently lacking.
  • Lopinavir/ritonavir: Protease inhibitor combo used in HIV infection with possibly some benefit in the treatment of SARS. Recent study showed no significant efficacy in severe Covid-19 disease. 
  • Interferon-alpha: An antiviral cytokine used against hepatitis B and C viruses. May be more effective for prophylaxis than post-exposure, based on experimental animal studies involving SARS.
  • Ribavirin: Another nucleoside analogue approved for hepatitis C (in combination with other drugs) and respiratory syncytial virus (RSV) infections but also evaluated in SARS and MERS. Has been reported to be active in vitro against Covid-19.
  • Sofosbuvir: Inhibits RNA-dependent RNA polymerase. Approved for treatment of hepatitis C, but also with in vitro activity against Covid-19.
  • Tocilizumab: Anti-interleukin-6 monoclonal antibody used in rheumatoid and giant cell arthritis. Theoretically, may mitigate cytokine storm observed in some patients during the later stages of Covid-19 disease.

Of course, there are many more drugs some of which would not be expected to be effective against Covid-19, based on what we so far know this virus. These include darunavir/cobicistat, oseltamivir, immunoglobulins, arbidol (an antiviral used in Russia and China vs influenza), angiotensin receptor blockers, stem cell therapy, convalescent plasma, and traditional Chinese medicine.

Remember corticosteroids are currently not recommended in the absence of other indications for their use (see related PEARL).

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References

  1. US National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=2019nCoV&term=&cntry=&state=&city=&dist
  2. Li Guangdi, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery 2020; Feb 19, 2010. https://www.nature.com/articles/d41573-020-00016-0
  3. Harrison C. Coronavirus puts drug repurposing on the fast track. Nature Biotechnology 020, Feb 27. https://www.nature.com/articles/d41587-020-00003-1
  4. Velavan TP, Meyer CG. The COVID-19 epidemic. Tropical Medicine and International Health 2020;25:278-280. https://onlinelibrary.wiley.com/doi/full/10.1111/tmi.13383
  5. Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sciences 2020;248. 11747. https://www.sciencedirect.com/science/article/pii/S0024320520302253
  6. Wang Y, Wang Y, Chen Y, et al. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol 2020;March 5. https://www.ncbi.nlm.nih.gov/pubmed/32134116
  7. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2029 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://www.ncbi.nlm.nih.gov/pubmed/31986264
  8. Paules CI, Marston HD, Fauci AS. Coronavirus infections—More than just the common cold. JAMA 2020;323:707-78. https://jamanetwork.com/journals/jama/fullarticle/2759815
  9. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research 2020;177. 104762. https://www.sciencedirect.com/science/article/pii/S0166354220301145
  10. Gurwitz D. Angiotensin receptor blockers as tentavie SARS-CoV-2 therapeutics. https://www.ncbi.nlm.nih.gov/pubmed/32129518/
  11. Wang M, Cao R, Zhang L, et al. Remdesivir and chlorquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020;30:269-71. https://www.nature.com/articles/s41422-020-0282-0
  12. Roques P, Thiberville SD, Dupuis-Maguirara L, et al. Paradoxical effect of chloroquine treatment in enhancing Chikungunya virus infection. Viruses 2018;10, 268. https://www.ncbi.nlm.nih.gov/pubmed/29772762
  13. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020;March 3. https://jamanetwork.com/journals/jama/fullarticle/2762688
  14. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; March 5. https://www.nejm.org/doi/full/10.1056/NEJMoa2001191
  15. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020. March 9. https://www.ncbi.nlm.nih.gov/pubmed?term=32150618
  16. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl M Med 2020, March18. DOI:10.1056/NEJMoa2001282. https://www.nejm.org/doi/full/10.1056/NEJMoa2001282

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What existing drugs are currently being evaluated or repurposed for treatment of Coronavirus (Covid-19) infection?

Can my patient contract influenza more than once in a season?

It’s not common but reinfection with influenza can definitely occur, either due to the same viral strain, or due to a different one altogether.

One study reported influenza reinfection due to H1N1 in otherwise healthy patients within 12-20 days of the original infection after an apparent period of full recovery. 1 There was no evidence of resistance to oseltamivir among isolates and all patients recovered after the second infection.

Reinfection with the same viral strain within 2-3 weeks of the initial bout of influenza shouldn’t be too surprising since it takes 4-7 weeks for antibody response to the infection to peak. 2 Reexposure to the same circulating strain of influenza virus (the season can last 6 weeks or longer) can then result in reinfection when the body hasn’t had enough time to make significant amount of protective antibodies following the first infection.

Another explanation is that more than 1 strains of influenza virus often circulate during any given season.   This places patients at risk of infection due to strains of influenza virus that do not confer significant cross-immunity between each other,  resulting in getting “the flu twice in 1 season.” 3

References

  1. Perz CM, Ferres M, Labarca JA. Pandemic (H1N1) 2009 reinfection, Chile. Emerg Infect Dis 2010;16:156-57. https://wwwnc.cdc.gov/eid/article/16/1/pdfs/09-1420.pdf
  2. Treanor JJ. Influenza viruses, including avian influenza and swine influenza. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 7th ed. New York: Elsevier; 2010. p 2265-2293.
  3. Rettner R. Can you get the flu twice in 1 season? Scientific American, LiveScience, February 4, 2018. https://www.scientificamerican.com/article/can-you-get-the-flu-twice-in-1-season/ . Accessed February 5, 2018.

 

Can my patient contract influenza more than once in a season?

Are neuraminidase inhibitors (NAIs) such as oseltamivir (Tamiflu) still effective for treatment of influenza in my hospitalized patient with greater than 48 hours of symptoms?

Although there are no randomized controlled studies, several observational studies support  the benefit of NAIs even when initiated after 48 h of onset of symptoms. 

Although the sooner NAIs are initiated the more likely the odds of a favorable impact on the course of influenza, the FDA approval of these drugs was based on analysis of data in relatively healthy ambulatory patients not those who are often sicker and require hospitalization. 

A retrospective study reported improvement in survival even when treatment was delayed for 4-5 days after symptom onset (1). Other studies have reported more rapid viral clearance and clinical benefit in severe infections even when antivirals were initiated after 48 h (2).  

Collectively , these data suggest that in the presence of ongoing symptoms and likely active viral replication, NAI treatment should be seriously considered in hospitalized patients who are likely to have more severe disease.

In fact, CDC recommends  “initiation of antiviral treatment as early as possible” in hospitalized patients with influenza, and asserts that “antiviral treatment might be effective in reducing morbidity and mortality in hospitalized patients even if treatment is not started until >48 hours after onset of illness” (3).  

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References

  1. Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1) pdm09. Clin Infect Dis 2012;44:1198-1204. https://www.ncbi.nlm.nih.gov/pubmed/22843781
  2. Lee N, Ison MG. “Late” treatment with neuraminidase inhibitors for severely ill patients with influenza: better late than never? Clin Infect Dis 2012;55:1205-8. https://www.ncbi.nlm.nih.gov/pubmed/22843780
  3. CDC. Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR 2011;60 (RR01):1-24.
Are neuraminidase inhibitors (NAIs) such as oseltamivir (Tamiflu) still effective for treatment of influenza in my hospitalized patient with greater than 48 hours of symptoms?

Are GI symptoms such as nausea, vomiting, and diarrhea common in patients with influenza?

Typically, GI symptoms are more prominent in children with influenza than adults but during the H1N1 epidemic in 2009 (which has subsequently become endemic), up to 26% of hospitalized adults with H1N1 infection had abdominal pain or vomiting and up to 25% had diarrhea (1). 

In fact, H1N1 virus has been isolated from stool of adult hospitalized patients (2,3) and receptors of influenza virus have been identified in human GI epithelial cells, the correlation between GI symptoms and isolation of virus from stool is poorly defined (4).

Interestingly, the mechanism involved in influenza-mediated intestinal injury may have less to do with direct invasion of the intestinal mucosa by the virus and more to do with immune mediated changes  related to alterations in the intestinal microbiota induced by influenza virus infection itself (4,5)! 

Aside from direct or indirect effects of influenza virus on the GI tract, oseltamivir and non-steroidal anti-inflammatory use may also contribute to GI symptoms (4).

 

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References

  1. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med 2010;362:1708-19. https://www.ncbi.nlm.nih.gov/pubmed/20445182
  2. Yoo SJ, Moon SJ, Kuak E-Y, et al. Frequent detection of pandemic (H1N1) 2009 virus in stools of hospitalized patients. J Clin Microbiol 2010; 48:2314-2315. https://www.ncbi.nlm.nih.gov/pubmed/20375236
  3. Minodier L, Charrel RN, Ceccaldi PE, et al. Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know? Virol J 2015;12:215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676820/
  4. Shu Y, Li CK, Gao R, et al. Avian influenza A(H5N1) viruses can directly infect and replicate in human gut tissues. J Infect Dis 2010;201:1173-7. https://www.ncbi.nlm.nih.gov/pubmed/20210629
  5. Wang J, Li F, Wei H, et al. Respiratory influenza virus infection induces intestinal immune injury via microbiota mediated Th17 cell-dependent inflammation. J Exp Med 2014;211:2397-2410. http://europepmc.org/article/PMC/4235643
Are GI symptoms such as nausea, vomiting, and diarrhea common in patients with influenza?