Examining the hype vs the data
by Buzz Hollander MD (updated April 14, 2020)
There has been a lot of excitement over the recent media reports of hydroxychloroquine (HCQ), the regularly-used cousin to chloroquine, and its potential efficacy against COVID-19. I am receiving regular questions about it, so I thought it was worth posting my thoughts.
First of all, let’s start simple: viruses are hard to kill. Maybe because they are not alive to start with. There are dozens of clinically important viruses that no one ever reads about in the media – respiratory syncytial virus, coxsackievirus, parainfluenza virus, etc., etc.. None of these have curative treatments. Only a handful of viruses do – and it took years or decades of research to come up with them. We now have effective treatments for Hepatitis C and HIV, but the struggles with finding those medications are well-known. We have fair-to-middling treatments for herpes viruses and influenza. That’s about it. All these medications took a lot of time to develop. What are the chances we stumble onto a highly effective treatment for a novel virus like COVID19 by just throwing an old antimalarial like HCQ at it? Low.
I don’t want to be “That Guy” in medicine who downplays every possible intervention that is not tried and true until the evidence finally becomes overwhelming and then finally admits “I guess the stuff works okay.” I am encouraged by the Gautret et.al. study from France (https://www.sciencedirect.com/science/article/pii/S0924857920300996), and hopeful from the rather vague data coming from China per the Gao, Tiang, and Yand report (https://www.biosciencetrends.com/downloadpdf/1883). However, if you actually look at the reports, and not the media buzz around them, they are not exactly “good science.” I started med school in 1998, and in the years since then I can’t count how many times there has been great excitement over the next cure for cancer, Alzheimers, heart disease, etc., based on laboratory research, high quality animal studies, or small scale human studies. They almost never pan out! In those 22 years, I can count on the fingers of one hand the genuine pharmaceutical advances that have been made that would really be considered “game-changers” like the Gautret article implies HCQ will be. That’s why I remain on the sidelines with this one: history suggests it will fail once exposed to more rigorous testing.
The Gautret study was small (42 patients); its data was corrupted (6 of the “treatment arm” patients left the study – 3 of them ICU-bound and 1 of them for the Next World – so 4 treatment failures were not included in the rosy summary); the treatment arm and control arm patients were not the slightest bit randomized (people unwilling to take a novel treatment were the “control” arm) nor were they equal (different patients were at different stages of disease, and the test group was twice as likely to be symptomatic and three times as likely to have pneumonia). Clearly the closer to disease peak you are in a study, the closer you are to either dying or clearing the disease – and since the study was evaluating the rate of disease clearance after 6 days on HCQ, treating more progressed people means you might have a bias towards finding cure (or death, which led to exclusion from the study results!). Even the treatments were different; some treated patients were given an antibiotic, azithromycin, leaving us wondering how much of a role this combination might have played. This is not to say there is no way HCQ was helping these patients; this is to say that when we have more data, I would bet my last dollar it will not be quite so positive.
On the bright side, HCQ is inexpensive and fairly well tolerated. I say “fairly” as I have had a good number of patients with autoimmune disease who were put on HCQ and did not stay on it for a variety of reasons – but rarely serious reactions and never for the retinal damage that is a well-documented but rare adverse effect of the medication. It is also difficult-to-impossible to order HCQ now, since there was a rush on it with the recent news. When supply lines are restored, would I treat someone with serious COVID-19 disease with it? Sure! Would I be optimistic it will be the “game-changer” that will save the patient? No. Multiple studies are underway in the US right now; we can hope more positive news emerges from them, like it lowers infections rates in health care workers who are being regularly exposed (that would help the health care workers AND the health care system AND their patients, a lot!), or that it can be used early in the course of disease to prevent serious complications. We simply do not have this data yet. But here’s to hoping… just with a grain of salt sprinkled over my newspaper.
UPDATES as of April 14, 2020: A small study of 30 not seriously ill COVID-19 patients in China was published soon after I wrote this that was rather discouraging – the study group receiving HCQ did not fare better than the control group, although both received “standard therapies” which may have muddied the water: http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43f8625d4dc74e42bbcf24795de1c77c.pdf .
Also discouraging are recent reports of a Brazilian study of HCQ’s precursor medication, chloroquine, being stopped early due to an unacceptable increase in heart arrhythmias. While they are less common with HCQ, this remains a concern, especially when combined with another medication, azithromycin, that has been known to cause the same arrhythmias, sometimes fatal, on its own.
On the other hand, on the auspicious day of April 1rst, another study from China was more positive: https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v2.full.pdf . In it, 62 hospitalized COVID-19 patients were randomized to receive HCQ for 5 days, or only standard treatment. In ten days after admission, 25/32 of the HCQ group was better vs 17/32 of the control group. The 4 patients who progressed to “serious disease” all were in the control group. Encouraging, yes; “game-changing”, maybe not. That of 62 patients sick enough to be hospitalized, only 4 progressed to serious disease might be a red flag that this was not a representative population; we might have expected this number to be closer to 20 in a representative sample based on China’s hospitalization rate being about triple its ICU rate. I will also note that this study reports that none of their area 80 lupus patients on HCQ had been hospitalized with COVID-19; and that of their 178 hospitalized patients, none had lupus. While this sounds nice, it is important to remember that a case series of 80 patients for a disease that sickened a small proportion of the populace is very, very small; and that lupus affects only 1/10th of one percent of the Chinese population. While this sort of headline makes great news copy (“LUPUS PATIENTS ON PLAQUENIL DON’T GET COVID-19!”), it also reminds one of the old joke: “What are you doing?” “Hunting lions.” “But there are no lions here.” “See – it’s working!”
The bottom line: as of mid-April, despite certain well-publicized claims to the contrary, we lack reliable evidence that HCQ is a useful tool against COVID-19; and that even if effective, it may only be marginally so.