04/16/2020
From the Nevada State Medical Association. This is very scientific, but worth reading.
An excellent update on Hydroxychloroquine, written by my esteemed colleague, Dr F. Kevin Murphy. Dr. Murphy is a leader in the Washoe County Medical Society and Nevada State Medical Association.
Hydroxychloroquine in the treatment of COVID-19
Very few mothers name their daughters Pandora, for it was she whose curiosity overcame her good judgment when she opened the forbidden box. Out flew all the worst afflictions of humankind. Here we will only name one, which waited millennia to show itself: COVID-19. However, beneath the lid of
Pandora’s box was trapped one bright spirit who did not escape, named Elpis, or Hope. Now comes hope for those afflicted with COVID-19, a drug that has meant much more than hope for our patients with rheumatoid arthritis and
systemic lupus erythematosus. Unfortunately, its effectiveness for COVID-19 is based on little more than hope. Much more promising therapies for this disease await testing, but what are
we to do while we wait, as we see patients with COVID-19 dying in front of us, as we struggle helplessly, hopelessly, to save them?
Let us examine the reasons for considering hydroxychloroquine for treating these patients. Early in the current pandemic, Didier Raoult’s distinguished group at the University of Marseille pointed out theoretical reasons for
considering chloroquine or hydroxychloroquine (Devaux et al.). Namely, in vitro these drugs inhibit the replication of a wide variety of RNA viruses, including polio, influenza, dengue, Zika, chikungunya, Lassa, rabies and Ebola. In the case of SARS-CoV1, the agent of the SARS epidemic of 2003, they interfere with the glycosylation of the cell surface viral receptor, ACE2, thus blocking attachment of the virus to cells in culture. After viral cell entry, fusion with endosomes is a critical step toward replication, and alkalinization of the endosome by chloroquine and hydroxychloroquine prevents this in the case of
some other RNA viruses, e.g Flaviruses. But SARS-CoV2? Maybe. Chloroquine also acts in the Golgi apparatus from which intracellular budding of coronaviruses takes place. This process depends on proper localization of the virus M protein within the Golgi complex. Chloroquine may impair this process
and interfere with viral intracellular budding. While such a mode of action pertains to dengue and herpes simplex viruses, this has not been shown for SARS-CoV2. On the other hand, early in the pandemic, Chinese investigators demonstrated in vitro activity of hydroxychloroquine against SARS-CoV2 (Liu et
al.)
The immunomodulatory effect of these drugs is well established and may be a help or a hindrance in COVID-19. By interfering with TNFα, IL1 and IL6 (Jang et al.), they may modulate the cytokine storm that seems to be fatal in
many cases of severe COVID-19. On the other hand, by interfering with interferon (IFα, IFβ, IFγ) (Farias et al.), chloroquine and hydroxychloroquine may be deleterious in acute COVID-19. Despite attractive hypotheses deriving from sophisticated in vitro studies, Devaux et al. admit “The antiviral properties of chloroquine described in vitro have sometimes been confirmed during treatment of virus-infected patients but
have not always been reproduced in clinical trials depending on the disease, the concentration of chloroquine used, the duration of treatment…”. For example, the in vitro activity of chloroquine against MERS-CoV has not been borne out in clinical trials in MERS-CoV disease.
So what clinical data supporting the use of hydroxychloroquine or chloroquine exists? Very little. Following quickly on their theoretical advocacy of hydroxychloroquine, the Raoult group threw together a small, quick and dirty trial in which they showed that 70% of 20 treated cases had cleared
SARS-CoV2 by a week of therapy as compared to 13% of 16 controls (p0.05). The mean date of conversion to negative was 4 days in the HCQ group and 2 days in the control group. Both groups became afebrile within a day of starting the study and all improved, so the study was too small and the patients too mildly ill to assess outcome.
So what are we left with? No outcome data on which to base a choice to use hydroxychloroquine, some interesting molecular data, most of it indirect and pertinent to other RNA viruses, safety data in non-COVID-19 patients that suggests that toxicity is reserved for longer courses of therapy, except for QT
interval prolongation, which we can monitor easily in the ICU. Of course, if we throw in azithromycin that is a greater threat. We do not have safety data in severely ill COVID-19 patients who commonly have a SARS-CoV2 cardiomyopathy with persistently elevated troponins throughout their course in
the ICU. Thirty-one % of those admitted to the ICU among the first 41 cases in Wuhan had elevated troponins (C. Huang, et al.) Of 138 patients with novel Coronavirus pneumonia admitted to Zhongnan Hospital of Wuhan University
in January, 16.7% had arrhythmias and 7.2% had acute cardiac injury (D. Wang et al.). In a study of the 52 most critically ill patients with COVID-19 pneumonia admitted to Jin Yin-tan and Wuhan Pulmonary Hospitals in January, Yang et al. reported that 23% had acute cardiac injury; they excluded
3 patients who died of cardiac arrest in transport or immediately after admission. Zhou et al. reported that of their 191 patients hospitalized in Wuhan, 17% had acute cardiac injury, 1% of those who survived and 59% of those who did not; the mean peak troponin of those who died was 290.6 and of
those who survived, 3.8. Are these patients at higher risk for QT prolongation and torsades de pointes? It would seem likely.
These are the scientific issues surrounding the use of HCQ for COVID19, but there are also ethical issues. Early reports suggesting its use for COVID-19 led to an explosion of prescribing for questionable use, such as prophylaxis, for which there is no data whatsoever, and for mild disease in outpatients at low risk. This led to a shortage that threatens our patients who depend on HCQ for management of rheumatoid arthritis and systemic lupus erythematosus (www.washingtonpost.com/business/2020/03/20/hospitalsdoctors-are-wipingoutsupplies-an-unproven-coronavirus-treatment). Patients report inability to refill their prescriptions, and abrupt withdrawal from HCQ can lead to flares of these diseases (Canadian Hydroxychloroquine Study Group; Koh et al.) In the case of lupus, that can mean transverse myelitis or
acute renal failure due to lupus nephritis. Lupus flares can occur within 2 weeks of discontinuation of the drug. Widespread use of HCQ for mild COVID19 disease or prophylaxis may also deny the use of the drug for more seriously affected patients with COVID-19 as well. It may threaten the integrity of controlled trials that will actually inform us of the safety and effectiveness of this drug in COVID-19, such as the large study currently enrolling at Henry Ford Hospital in Detroit. The NIH has just begun to enroll the first of 500 patients in a multicenter study of HCQ. While manufacturers are endeavoring to upscale production to meet this new demand (Yasdani & Kim) hospitalization rates for COVID-19 are also increasing sufficiently to consume
the increasing production in the next 2 months. Patients with life-threatening flares of disease may arrive at our doors just when hospitals are filled to capacity with COVID-19.
The scientific rationale for investigating HCQ in COVID-19 is
unassailable, but the rapid reporting and dissemination of poorly designed clinical studies of the drug, its previous availability and low cost, have led to a crisis in availability for the patients who need it most. We are therefore not alone in cautioning our colleagues to accept the governor’s and Board of Pharmacy’s temporary restrictions on its use to those who really need it, i.e. patients already taking it for rheumatoid arthritis and lupus, and possibly patients hospitalized for COVID-19. As physicians, we would like more latitude for the use of our clinical judgment. However that privilege also carries with it the responsibility not to rush to judgement. As the pandemic unfolds, we will learn whether HCQ has
any value or sufficient safety in COVID-19 management and prophylaxis.
Until then, we should shift a little of our patient-centered focus to a community focus, remembering that the patient in front of us is not the only patient. Remember that if the use of HCQ is vastly expanded, then its relative safety in small numbers of patients who generally benefit will give way to serious side
effects in a small percentage of a large number who may not benefit at all. A small percentage of a large number may be a large number. We are not alone in discouraging the widespread use of HCQ for treatment or prophylaxis of COVID-19 (Yasdani et al., Kim et al.) Vice President Pence has received a letter from the American Academy of Dermatology, American College of Rheumatology, Arthritis Foundation, and the Lupus Foundation of America pleading for preserving “access to these medications for those patients whose lives and productivity depend on them”.
The president of the AMA has called for an end to promotion of HCQ for COVID-19, citing its hazards. The president of the American College of Physicians has publicly called on physicians to “listen to the science” and
refrain from using HCQ in COVID-19 until its safety and effectiveness in the disease are known. The American Thoracic Society has recommended confining the use of HCQ to those cases of COVID-19 with “severe pneumonia”. The American Medical Association, American Pharmacists Association, and
American Society of Health-System Pharmacists issued a joint statement on March 25 taking a position against inappropriate ordering, prescribing or dispensing of medications to treat COVID-19, including HCQ, and becoming responsible stewards of a limited resource.
What are we to do while we wait for reliable scientific data on HCQ? We will continue to use HCQ carefully in critically ill patients in the ICU, consistent with our governor’s order. We will check the QT interval assiduously and discontinue the drug when it rises above 0.450. We may avoid the drug in
patients with persistently elevated troponin I or other evidence of cardiac injury. When our patients die of cardiac arrest as many of them have, we will review our use of HCQ in those patients. For the eager among us, read the
review of promising therapies by Sanders et al. from UT Southwestern’s Division of Infectious Disease in JAMA this week. Patience and good judgment are not the spirits that Pandora was able to retain in her frightening little box. Somehow we must find them, as we face the terrors of the COVID-19 pandemic. Hope is needed, but is not enough.
