I am involved in planning our regional response for COVID-19. I would appreciate feedback on the reasoning outlined below. I have convinced myself that it makes sense, but am looking for independent feedback and have been struggling to get it.
I would greatly appreciate it if someone could knit-pick this with a fine tooth comb and try and find some mistake I've made (off by a order of magnitude?, etc.), or provide argument why this is a dumb idea.
Outbreaks of human coronavirus infections have often been centered around hospitals and health-care providers in their early stages. This was seen with SARS-CoV-1 in 2003-04,<1>, <2> MERS-CoV in 2018-19<3>, and SARS-Cov-2 in 2020.<4> It is presumably related to the non-specific symptoms of these illnesses early in their clinical course coupled with close contact of health-care providers with infected patients in hospital, and inadequate personal protective equipment use.<3>
Infection of health-care providers with highly morbid human coronaviruses is problematic not just due to their subsequent role in propagating infection among vulnerable inpatients, but due to the impact of illness in health-care workers on adequate staffing during an epidemic. This would be expected to be even more pronounced during an outbreak of SARS-CoV-2, given the potential for asymptomatic spread of disease.<5>
As a result, available pre- and post-exposure prophylaxis of health-care workers for SARS-Cov-2 would be ideal. An effective agent would be expected to both prevent spread of disease in hospitals, and maximize the workforce available to provide patient care during an epidemic situation.
To date, there are no known effective treatments for COVID-19, though a number of clinical trials are currently ongoing. The antimalarial chloroquine (CQ) has shown early promise among these. Preliminary results suggest the CQ is superior to control for shortening disease severity, inhibiting exacerbation of pneumonia, improving imaging findings, and improving virus-negative conversion.<6> No significant adverse events were noted in this cohort. As a result, treatment of COVID-19 with CQ has been recommended for inclusion in Chinese national clinical practice guidelines. While CQ has been used to treat malaria and rheumatological diseases for decades, it’s mechanism of action is complex and not fully understood. Due to its basic pKa, CQ preferentially accumulates within cellular lysosomes, subsequently causing lysosomal pH to increase, altering lysosomal function. This has a large number of downstream cellular effects.<7>
In SARS-CoV-1 infection, viral infection is mediated by viral Spike glycoprotein binding to the membrane-bound exopeptidase, Angiotensin Converting Enzyme 2 (ACE2), which is expressed at high levels in Type II Alveolar Cells in the lungs. This binding allows the virus to be phagocytosed into cellular endosomes, with subsequent viral entry into the cytoplasm being dependent on an acidic endosomal pH.<8> Specifically, membrane-fusion is dependent on cellular proteases such as cathepsin B and L splitting viral S-protein into S1 and S2 subunits, with the resulting S2 subunit mediating membrane fusion. Cathepsin B and L activity are inhibited by an elevated endosomal pH.
In vitro studies of SARS-Cov-1 infection in a primate cell line showed that CQ was an effective pre- and post-infective antiviral agent.<9> Specifically, CQ-induced altered ACE2 glycosylation was felt to be the mechanism by which pretreatment prevented infection (by inhibiting S-protein binding and subsquent phagocytosis), and CQ-induced increased endosomal pH (and resulting inhibited protease activity) was felt to be the mechanism by which treatment of existing infection had an antiviral effect.
SARS-Cov-2 infection has been shown to be mediated by the same pathophysiological process as SARS-Cov-1.<10> Recent studies of CQ in vitro with SARS-CoV-2 infection of primate cell lines confirmed the same pre- and post-infective antiviral properties were present as with SARS-CoV-1.<11> Specifically, the EC90 was found to be 6.9uM, and the EC50 was 1.13uM.
Serum concentrations of CQ can be found in this range in patients on CQ for other therapeutic indications. Patients taking 500mg/d of CQ salt (8.3mg/kg/d) were found to have a serum concentration of CQ of 10uM.<12> Unfortunately, patients taking this high of dose of CQ for prolonged periods of time are at risk of developing retinopathy – the maximum daily dose of CQ recommended by guidelines from the American Academy of Ophthalmology are 2.3mg/kg/d based on actual body weight.<13>
Fortunately, CQ has an extremely high volume of distribution. As a result of this, tissue concentrations are significantly higher than serum levels. In the lung, the target organ of SARS-CoV-2 infection, concentrations of CQ are 200-1200x serum values.<14> This would suggest that a steady-state serum concentration of CQ much lower than the EC90 of SARS-CoV-2 would be associated with a target tissue concentration above the EC90. The steady-state serum concentration of 500mg of CQ taken once weekly is 0.1uM,<12> which given the above reasoning, would be expected to lead to a lung concentration above the reported EC90 of SARS-CoV-2. 500mg of CQ taken once weekly is the malaria prophylaxis dose of CQ. This dose is extremely well-tolerated with minimal side-effects in most patients, and well below the threshold dose known to be associated with an increased risk of retinopathy.
Given that the duration of pre-exposure prophylaxis could be on the order of months, the use of a dose well below the threshold associated with an increased risk of retinopathy is preferred. If exposure to SARS-CoV-2 cases is relatively infrequent, then a short course (say, the duration of the potential incubation period of infection) of a higher dose could be used a form of post-exposure prophylaxis, allowing maximal tissue concentrations in the days after exposure, while minimizing possible side-effects. In healthcare providers providing daily care to patients with confirmed SARS-CoV-2 infection for a prolonged period of time, this higher dose could still be taken regularly with minimal risk of side-effects, provided the total treatment duration was less than a year.
CQ also has an extremely long half-life, in the order of 3-5 days. This unfortunately means that therapeutic steady state concentrations are not reached until after weeks of therapeutic dosing, unless a loading dose is received.<12> When CQ is used to treat acute malaria, a loading regimen of 1000mg at 0h, 24h, and then 500mg at 48h is used as a result. This dosage schedule has been shown to rapidly increase serum levels in humans, with a serum concentration greater than 1uM achieved continuously within hours of the first dose.<15> The implication of this is that if CQ was used for post-exposure prophylaxis, a loading dose would be required. Given the rapidly changing environment of an epidemic, waiting several weeks to achieve a therapeutic steady state concentration may also be impractical, suggesting utility in using a loading dose even for pre-exposure prophylaxis dosing.
Based on the above reasoning, I would suggest the following dosing regimens of CQ if used prophylactically in healthcare workers to prevent SARS-CoV-2 infection:
Pre-exposure prophylaxis: Loading dose: 1000mg of chloroquine salt (600mg base) taken at 0-hours, 24-hours, and then the first 500mg dose (300mg base) taken at 48-hours. Ongoing treatment: 500mg chloroquine salt (300mg base) taken once weekly.
Post-exposure prophylaxis: Loading dose: 1000mg of chloroquine salt (600mg base) taken at 0-hours, 24-hours, and then 500mg of chloroquine salt (300mg base) at 48-hours. Ongoing treatment: 500mg chloroquine salt (300mg base) taken daily for 12 days.
Hydroxychloroquine (HCQ) is nearly identical in structure to CQ and has a similar mechanism of action and therapeutic efficacy in rheumatological and infectious diseases. Like CQ, it also has a long half-life, and a very high volume of distribution. It is similarly concentrated in the lung, with tissue levels 2 orders of magnitude higher than serum levels at steady-state.<14> Kinetic studies of once weekly dosing show a nadir serum concentration of approximately 0.1uM.<16> However, the risk of retinopathy is somewhat lower with HCQ, with retinal toxicity only occurring at doses greater than 5mg/kg/day real body weight for several years. HCQ is also more readily available in some countries than CQ. While it would seem that HCQ should be as efficacious as CQ in preventing and treating SARS-CoV-2 infection, there are no data yet to support this, though a clinical trial using HCQ to treat COVID-19 is currently underway in China.<6> Were HCQ to be used for SARS-CoV-2 prophylaxis in health-care workers, the following dosing would seem reasonable:
Pre-exposure prophylaxis: Loading dose: 800mg of hydroxychloroquine salt (620mg base) taken at 0-hours, then 400mg (310mg base) taken at 6-hours, 24-hours, and 48-hours. Ongoing treatment: 400mg hydroxychloroquine salt (310mg base) taken once weekly.
Post-exposure prophylaxis: Loading dose: 800mg of hydroxychloroquine salt (620mg base) taken at 0-hours, then 400mg (310mg base) taken at 6-hours, 24-hours, and 48-hours. Ongoing treatment: 400mg hydroxychloroquine salt (310mg base) taken daily for 12 days.
It should be noted that the above reasoning is based solely on biological plausibility, which is an extremely low-level of evidence. Ideally, the suggestions made above would be verified clinically before usage. However, the expected minimal harm with the above dosing regimens, coupled with potential benefits in an epidemic situation, could support prophylactic usage in health-care providers even before clinical studies are performed.
Healthcare workers on coronavirus frontlines start to test positive
<1> M. Varia et al., “Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS) in Toronto, Canada,” Cmaj, vol. 169, no. 4, pp. 285–292, 2003.
<2> A. Wilder-Smith, M. D. Teleman, B. H. Heng, A. Earnest, A. E. Ling, and Y. S. Leo, “Asymptomatic SARS coronavirus infection among healthcare workers, Singapore,” Emerg. Infect. Dis., vol. 11, no. 7, pp. 1142–1145, 2005.
<3> J. A. Al-Tawfiq and P. G. Auwaerter, “Healthcare-associated infections: the hallmark of Middle East respiratory syndrome coronavirus with review of the literature,” J. Hosp. Infect., vol. 101, no. 1, pp. 20–29, 2019.
<4> D. Wang et al., “Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China,” JAMA – J. Am. Med. Assoc., pp. 1–9, 2020.
<5> D. Chang, H. Xu, A. Rebaza, L. Sharma, and C. S. Dela Cruz, “Protecting health-care workers from subclinical coronavirus infection,” Lancet Respir. Med., vol. 2600, no. 20, p. 2001468, 2020.
<6> J. Gao, Z. Tian, and X. Yang, “Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.,” Biosci. Trends, pp. 1–2, 2020.
<7> E. Schrezenmeier and T. Dörner, “Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology,” Nat. Rev. Rheumatol., 2020.
<8> D. A. Groneberg, R. Hilgenfeld, and P. Zabel, “Molecular mechanisms of severe acute respiratory syndrome (SARS),” Respir. Res., vol. 6, pp. 1–16, 2005.
<9> M. J. Vincent et al., “Chloroquine is a potent inhibitor of SARS coronavirus infection and spread,” Virol. J., vol. 2, pp. 1–10, 2005.
<10> Y. Wan, J. Shang, R. Graham, R. S. Baric, and F. Li, “Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS,” J. Virol., no. January, 2020.
<11> M. Wang et al., “Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro,” Cell Res., no. January, pp. 2019–2021, 2020.
<12> A. H. Mackenzie, “Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials,” Am. J. Med., vol. 75, no. 1 PART 1, pp. 40–45, 1983.
<13> M. F. Marmor, U. Kellner, T. Y. Y. Lai, R. B. Melles, W. F. Mieler, and F. Lum, “Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision),” Ophthalmology, vol. 123, no. 6, pp. 1386–1394, 2016.
<14> E. W. McChesney, W. F. Banks, and R. J. Fabian, “Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat,” Toxicol. Appl. Pharmacol., vol. 10, no. 3, pp. 501–513, 1967.
<15> E. Pussard et al., “Efficacy of a loading dose of oral chloroquine in a 36-hour treatment schedule for uncomplicated Plasmodium falciparum malaria,” Antimicrob. Agents Chemother., vol. 35, no. 3, pp. 406–409, 1991.
<16> H. S. Lim et al., “Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by plasmodium vivax,” Antimicrob. Agents Chemother., vol. 53, no. 4, pp. 1468–1475, 2009.
Source: Original link