AN OLD DRUG FOR THE NEW VIRUS
By: Dr. Andrea Savarino
Under the prevailing circumstances of uncertainty and limited options, I believe an old, cheap, oral, off-patented drug — chloroquine — should be considered for certain populations at high risk of exposure to the COVID-19 virus.
The history of Chloroquine (and its cousin hydroxychloroquine) dates back to 17th century Peru, where a related compound, quinine, was extracted from the bark of Cinchona trees and used to treat chills and fever. Chloroquine itself was synthesized in 1934 by Hans Andersag at the Bayer laboratories. During World War II, U.S. government-sponsored clinical trials demonstrated the antimalarial effects of the drug.
Chloroquine is now being studied in multiple clinical trials in China as a treatment for COVID-19, the disease caused by the SARS-CoV-2 coronavirus. China, Korea, and Italy have added it to treatment guidelines for patients infected with COVID-19. I believe there is sufficient evidence regarding the safety and efficacy of chloroquine to recommend making the drug immediately available to specific high-risk patient populations. More is known about chloroquine than nearly all new drug candidates which, by definition, lack human experience of both safety and efficacy. For this reason, chloroquine may be the one and only immediately available “stopgap” therapy, while potentially better drugs move through the development process. For the time being, chloroquine only needs to possess a superior risk/benefit profile relative to the status quo of no therapy. Chloroquine is also uniquely inexpensive at approximately $13 per day(1).
I believe that a compelling risk/benefit profile exists today for specific “high-risk” COVID-19 populations: 1) Health-care providers (HCPs) at high-risk for COVID-19 exposure, and 2) Housebound COVID-19 patients and their family members. Neither of these groups receives any therapy today. I am not aware of any clinical trials evaluating chloroquine (or any drugs) in these populations due to multiple hurdles, including complex “out of hospital” logistics and large sample size requirements.
Our recommendation has a close analogy and precedent with AZT, an old generic drug approved in 1987 as the first therapy for HIV. In the 1990s, many hospitals adopted AZT prophylaxis protocols for health care providers at high risk of HIV infection prior to the emergence of conclusive evidence from controlled clinical trials. The rationale was similar (superior risk/benefit versus doing nothing), as was the unique stopgap role of AZT treatment, while potentially better drugs moved through the development process. AZT played a vital role in the history of HIV.
Why might chloroquine be effective for COVID-19? In a 2006 paper from The Lancet Infectious Diseases, I discussed findings that chloroquine alters the sugar structure of ACE2, which the SARS Coronaviruses use to gain entry to cells(2). This altered structure inhibits the ability of SARS-CoV-2 to enter and infect cells. In 2020, Dr. Manli Wang discovered that chloroquine is effective in an in-vitro experiment at concentrations achievable by chloroquine doses routinely taken by Lupus patients(3).
Chloroquine also exerts broad-spectrum antiviral effects. Prior clinical trials of chloroquine have failed, such as the case of HIV/AIDS(11). I believe insufficient dosage may have been a critical reason. In 2006, I suggested that chloroquine doses of at least 500 mg/day would be required to combat SARS-CoV(2). For SARS-CoV-2, the Chinese Ministry of Health recommended a dose of 500mg twice daily(12). According to a summary report of a chloroquine clinical trial interim analysis, this dose appeared to be effective in the clinical management of COVID-19(13).
No drug is riskless, and such risks include both known and unknown toxicities. Unique to chloroquine, the risks here are predominantly known potential side effects: eye damage, heart complications, and impairment of the body’s ability to fight an infection. A short course of chloroquine therapy is very unlikely to cause these side effects.
The American Academy of Ophthalmology guidelines from 2011 state that eye damage is associated with 1000g of cumulative chloroquine intake and over 5-years of treatment(4). This is equivalent to 500 mg every day for five and a half years. A short two-week course of chloroquine for COVID-19 would be 14g, a miniscule amount of cumulative drug. Chloroquine could lead to a heart abnormality called “QT interval prolongation” and in very rare cases lead to more severe complications(5). However, rheumatologists believe potential risks of heart complications from chloroquine are lower than those of the eye. Finally, available evidence suggests chloroquine decreases risk of infections in patients with lupus(7,8,9), and it only dials down important immune molecules slightly in contrast to more powerful immunosuppressants such as corticosteroids(6).
We must also consider the risk / benefit of maintaining the status quo. Healthcare systems around the globe may become overwhelmed, leaving patients to fend for themselves. COVID-19 testing may continue to be inadequate. Alternative drugs may become supply-limited or reserved for severe patients. Remdesivir is a promising drug for COVID-19, but it is given intravenously and thus likely limited to severe hospitalized patients. Novel therapies and vaccines in development are likely at least one year away from an expedited FDA approval, even in a best-case scenario. Developing countries critical to eradicating COVID-19 will require an inexpensive drug like chloroquine.
I propose the following concrete actions to help curb this pandemic. Generic manufacturers increase production of chloroquine and hydroxychloroquine. Health care providers raise awareness of the favorable risk/benefit for the discussed patient populations. We all collaborate to generate clinical data on chloroquine in these populations as rapidly as possible.
Although randomized, double blind clinical trials are considered the gold standard of evidence, logistical challenges would likely preclude timely execution of these trials. I propose an unconventional, alternative idea that would put chloroquine in the hands of at-risk individuals and suspected patients quickly. Patients and HCPs would receive chloroquine on a voluntary basis. They would self-report drug use, symptoms, side effects, and hospital visits to an online data depository. Outcomes and risk/benefit could be assessed in real time, comparing the group which elects to take chloroquine versus the group that declines. This study would be observational in nature and far from perfect. Nevertheless, if chloroquine proves highly effective with minimal side effects, such a study is likely to reveal this signal, ignite broad use of chloroquine, and save many lives in the process.
My bottom line: If I were on the Princess Diamond cruise ship today and were fortunate enough to have a bottle of chloroquine, I would unequivocally elect to take the drug prophylactically. All high-risk individuals can and should be offered the same option immediately.
References
1) “Chloroquine Prices, Coupons & Patient Assistance Programs.” Drugs.com, www.drugs.com/price-guide/chloroquine.
2) Savarino, A., Di Trani, L., Donatelli, I., Cauda, R., & Cassone, A. (2006). New insights into the antiviral effects of chloroquine. The Lancet Infectious Diseases, 6(2), 67–69. doi:10.1016/s1473–3099(06)70361–9
3) Wang, M., Cao, R., Zhang, L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30, 269–271 (2020). https://doi.org/10.1038/s41422-020-0282-0
4) Yusuf, I. H., Sharma, S., Luqmani, R., & Downes, S. M. (2017). Hydroxychloroquine retinopathy. Eye, 31(6), 828–845. doi:10.1038/eye.2016.298
5) Chatre, C., Roubille, F., Vernhet, H., Jorgensen, C., & Pers, Y.-M. (2018). Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Safety. doi:10.1007/s40264–018–0689–4
6) Schrezenmeier, E., Dörner, T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol 16, 155–166 (2020). https://doi.org/10.1038/s41584-020-0372-x
7) Rempenault, C., Combe, B., Barnetche, T., Gaujoux-Viala, C., Lukas, C., Morel, J., & Hua, C. (2017). Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Annals of the Rheumatic Diseases, 77(1), 98–103. doi:10.1136/annrheumdis-2017–211836
8) Sisó, A., Ramos-Casals, M., Bové, A., Brito-Zerón, P., Soria, N., Muñoz, S., … Coca, A. (2008). Previous antimalarial therapy in patients diagnosed with lupus nephritis: Influence on outcomes and survival. Lupus, 17(4), 281–288. doi:10.1177/0961203307086503
9) Ruiz-Irastorza, G., Olivares, N., Ruiz-Arruza, I., Martinez-Berriotxoa, A., Egurbide, M.-V., & Aguirre, C. (2009). Predictors of major infections in systemic lupus erythematosus. Arthritis Research & Therapy, 11(4), R109. doi:10.1186/ar2764
10) Touret F, de Lamballerie X. (2020). Of chloroquine and COVID-19. Antivir Res, 177, 104762. doi:10.1016/j.antiviral.2020.104762.
11) Savarino A, Shytaj IL (2015). Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS. Retrovirology. 18;12:51. doi: 10.1186/s12977–015–0178–0.
12) Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. (2020). [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 43(0):E019. doi:10.3760/cma.j.issn.1001-0939.2020.0019.
13) Gao J, Tian Z, Yang X. (2020). Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. doi: 10.5582/bst.2020.01047