The Hydroxychloroquine Quandary
Written by Dr. Mark Lopatin
As a rheumatologist, I write many prescriptions for hydroxychloroquine (HCQ) for my rheumatoid arthritis (RA) and lupus patients; HCQ used to be a quiet drug minding its own business, avoiding the limelight. Until now.
With the onset of COVID-19, HCQ has suddenly taken center stage, with many opinions on using it to treat Covid. Our president has declared it a “game changer”, and he has recently admitted to the world that he is taking the medication himself as prophylaxis after having been exposed. There are no well done studies looking at efficacy, but many observations have been reported.
The Marseilles study,1 the most frequently cited study promoting HCQ, was a small study assessing the presence of virus on nasal swabs at six days. 26 patients received HCQ, but data was excluded in six patients. Clinical status was not assessed. Six patients also received Azithromycin (AZ). Eight of the 14 patients who received HCQ alone had negative viral swabs at six days. All six who received both drugs cleared the virus. This study was contradicted by another French study2 which showed no change in viral presence in 8/10 patients treated with both drugs.
Dr. Vladimir Zelenko has reported great success3 in treating several hundred patients with a regimen of HCQ, AZ and zinc. His report has been criticized4 for lacking adequate diagnostic information and for not being of long enough duration, but it does represent a larger sample size than other studies and shows excellent results. It is unclear whether his observations constitute adequate evidence of efficacy.
A Chinese study5 assessed 62 patients with Covid. 31 received traditional therapy and 31 received an additional five day course of HCQ. The study6 cited improvement in time to clinical recovery, changes in body temperature and cough in the HCQ group. 81% of the patients in the HCQ group demonstrated improvement in pneumonia compared with 58% of the control group. Furthermore all 4 patients who developed severe illness were in the control group.
Another French study7 of 1061 patients treated with HCQ and AZ found that only 4.3% had poor clinical outcomes with only 8 deaths. The study was retrospective with no control group. The poor outcome patients were considerably sicker at baseline and had a mean age of 69, compared with a mean age of 42 in the patients who did well. The study suggests benefit for HCQ/ AZ, but has significant flaws as noted.
Other support for using HCQ8 comes from the Indian Council of Medical Research, which recommends a prophylactic regimen9 for health care workers caring for Covid patients. It is unclear what data was used to make this recommendation.
A subsequent trial was done in China looking at prophylaxis.10 205 patients with a known exposure to Covid were treated with HCQ 400 mg/ day for 14 days and were quarantined. None were + for virus at 14 days. There were no significant adverse events although 32 patients reported minor side effects. The study supports prophylaxis with HCQ in people with known exposure.
Alternatively, The Centre for Evidence-Based Medicine at the University of Oxford noted 142 ongoing trials11 evaluating HCQ and chloroquine in the treatment of Covid. They reviewed the five studies with published results and concluded that:
“Current data do not support the use of hydroxychloroquine for prophylaxis or treatment of COVID – 19. There are no published trials of prophylaxis. Two trials of hydroxychloroquine treatment that are in the public domain, one non peer reviewed, are premature analyses of trials whose conduct in both cases diverged from the published skeleton protocols registered on clinical trial sites. Neither they, nor three other negative trials that have since appeared, support the view that hydroxychloroquine is effective in the management of even mild COVID-19 disease.”
A VA study12 retrospectively analyzed 368 patients who received either HCQ, HCQ + AZ or no HCQ (32% of these patients received AZ) and reported a higher incidence of death and mechanical ventilation in the HCQ and HCQ + AZ groups. The study is seriously flawed however as there were significant differences between the 3 groups in terms of blood pressure, lab tests (creat, ALT, Hct, CRP) and baseline respiratory status. Hydroxychloroquine, with or without azithromycin, was more likely to be prescribed to patients with more severe disease.
The next question is whether HCQ is “safe”. My patients typically take HCQ for a number of years. I do not get screening EKG’s and do not routinely discuss cardiac risks as they are felt to be minimal. My rheumatology colleagues concur in this regard. I have had only one patient who had to stop HCQ due to a prolonged QT interval. Eye toxicity, although unlikely, remains the major concern with prolonged use. I feel the drug is safe enough to use empirically in some patients in whom I suspect RA or lupus even without proof.
There are potential downsides however in using HCQ to treat COVID.
Our president has stated “what do you have to lose?” First is that although the drug is relatively safe, the risk of adverse effects is not zero. I have had patients experience gastrointestinal (GI) side effects and severe rash.
One study examined 84 COVID patients13 treated with the combination of HCQ and AZ, looking at the incidence of QT prolongation. It is unclear how to interpret the results. 11% of these patients had an increase in QT interval to greater than 500 ms, placing them at high risk for arrhythmias, yet none of these patients actually developed arrhythmia. One cannot draw any conclusions from this study regarding risks of HCQ alone.
Another report concluded the following:14
“Worryingly, significant risks are identified for combination users of HCQ+AZ even in the short-term as proposed for COVID19 management, with a 15-20% increased risk of angina/chest pain and heart failure, and a two-fold risk of cardiovascular mortality in the first month of treatment.”This study was retrospective with 62 authors looking at over a million patients. The sheer volume makes the conclusions suspect in terms of consistency.
A trial in Brazil15 compared the risk of toxicity of Chloroquine using high and low doses. The study found that those in the high dose group had a significantly increased incidence of death and the study was stopped prematurely on that basis. This has been used as an argument against the use of chloroquine and by proxy HCQ, but the question remains as to whether we should not be using these drugs at all based on toxicities noted with very high doses, or whether we should simply not use those high doses.
Finally, a study done at Beth Israel16 looked at the incidence of QT prolongation in 90 patients receiving HCQ or HCQ + AZ. They found that 21/ 90 patients developed either prolonged QT intervals greater than 60 ms, or QT intervals greater than 500 ms placing them at greater risk for arrhythmias. One of these patients developed Torsade’s, which the authors state has not been noted elsewhere in the literature.
In view of these and other studies, the American Heart Association, American College of Cardiology and the American Heart Rhythm Association have concluded that we should avoid using both HCQ and AZ in patients with baseline congenital long QT syndrome or QT > 500 ms and that patients using both should have monitoring of their cardiac rhythm and QT interval.
A second downside separate from possible adverse drug reactions is that promoting HCQ as a potential cure sets patients and their families up for disappointment if reality fails to meet expectations.
Finally, the most significant downside is the inability of some lupus and RA patients to obtain HCQ. Additionally, prior authorizations, now required when prescribing HCQ, can result in further delays for patients even if the drug is available.
The main question here is whether there is “enough” evidence of efficacy of HCQ in treating Covid to warrant the potential downsides. That depends on one’s definition of the word “enough”.
What is especially troubling is that how one defines “enough” seems to depend on their political leanings. Those on the right tend to be staunch supporters of HCQ while those on the left emphasize the downsides. Both the efficacy and toxicity of this drug have been amplified in order to serve individual political narratives.
I oppose this “politicization” of medical treatments.
Despite strong opinions on both sides, we do not yet know how well HCQ works in treating Covid, and if so, exactly when and how to use it. That does not preclude its use. There are numerous circumstances where physicians treat patients empirically. Not knowing if a drug works is different than knowing that it doesn’t. Ideally, we should wait for a properly designed study, but in a crisis situation, can we afford the delay? Again, it depends on how one defines “enough.”
Medications should not be used for political capital. HCQ should not be promoted as a “game-changer” based on a “good feeling”. Politicians and media should not be cherry-picking the data to suit their underlying agendas. Treatment decisions should be made by physician and their patients without interference. Public policies forbidding the use of HCQ and threatening physicians are not appropriate.
Ultimately we will have answers to the HCQ quandary, but for now, physicians must care for our patients as best we can with the information available to us. Physicians are the ones who must do risk/ benefit analysis and inform our patients. That is what we are trained to do. That is what we do every day. COVID-19 should not change that.
What In The Heck Is A Prolonged QT?
The electrocardiogram (also known as an EKG or ECG) is a tracing that consists of different hills, peaks and valleys that are named alphabetically from the letter “P” through “U.”
The P wave represents the electrical activity present when the atrial muscles contract.
The QRS complex represents the left and right ventricle depolarization.
The T wave is the time that it takes for the ventricles to repolarize.
The qT interval is the time between the beginning of the QRS to the end of the T wave. It represents the time in which the ventricles contract and then relax. If a qT interval is too long or too short it puts the person at risk for abnormal heart rhythms.
Some people are born with an inherited form of an unusually long qT interval. Others can develop a long qT when they become dehydrated, develop electrolyte abnormalities or take certain drugs. Those most at risk for arrhythmias are those with an underlying congenital form of prolonged qT who take drugs that prolong the interval.
Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL, Schwartz PJ, Towbin JA, Vincent GM, Lehmann MH. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation. 1995 Nov 15;92(10):2929-34.
Note: since the writing of this article, there have been new studies reported on HCQ, which are not reflected in this article.