Two preprints* were released yesterday that add to the growing evidence that hydroxychloroquine is not useful in COVID-19, contrary to all the hype.
Please note that I am not a medical doctor and this is not medical advice. A more detailed disclaimer can be found at the bottom of the page.
Let's take a look at the data.
A Second RCT Confirms No Effect of Hydroxychloroquine
The first randomized controlled trial (RCT) of hydroxychloroquine was published in Chinese. I used Google Translate to read it, and analyzed it here. It was a small study done in 30 patients and found no effect of 400 mg hydroxychloroquine once a day for five days on clearance of the virus after seven days or two weeks.
A preprint of a new RCT was released yesterday. It was larger and used higher doses.
This new trial used 1200 mg a day for three days followed by 800 mg a day for a total treatment time of two weeks for mild and moderate cases and three weeks for severe cases.
They originally designed the study to include 360 patients, but were only able to admit 191. Of those, 41 were excluded for reasons such as allergies to hydroxychloroquine or chloroquine, liver or kidney diseases that hurt the metabolism and elimination of hydroxychloroquine, cognitive and mental deficits, and women who were pregnant or nursing. That left 150 patients who were randomly allocated, 75 to a group that received only the standard of care, 75 to a group that received the standard of care plus hydroxychloroquine.
Patients were randomized an average of 17 days after they had first gotten sick, although 33 of them (22%) were randomized less than seven days after getting sick.
Their primary endpoint was clearance of the virus.
Their secondary endpoints included a composite score for resolving “symptoms,” which included resolving fever, normalizing the oxygen content of the capillary blood, and recovering from respiratory symptoms (nasal congestion, cough, sore throat, phlegm, and shortness of breath). Another secondary endpoint included normalization of lab markers of inflammation, such as C-reactive protein (CRP), the erythrocyte sedimentation rate, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha).
No Effect on Viral Clearance or Symptom Alleviation
Hydroxychloroquine had no effect on the clearance of the virus at any time point, including 4, 7, 10, 14, 21, or 28 days after randomization.
Their BMI, preexisting conditions, baseline inflammatory markers, use of other drugs, and whether they were randomized before or after 7 days of being sick all had no effect on the results.
Hydroxychloroquine had no effect on whether their symptoms were alleviated by the end of the trial, or the average time it took to reach symptom alleviation.
Fishing for Significance
The authors did claim that symptoms were alleviated faster anyway on the basis that symptom relief was higher in the hydroxychloroquine group than in the control group during the second week. However, this was not very impressive and it was not statistically significant. It is almost fully explained as follows: roughly 15% of people achieved symptom alleviation on day 9 with hydroxychloroquine, while their counterparts in the control group caught up on day 10; another 10% in the hydroxychloroquine group achieved symptom alleviation on day 11, while their counterparts in the control group caught up on day 14.
Since this was not statistically significant, the authors performed a subgroup analysis on it. Along with 13 other comparisons, they looked at the 28 people (19%) who were not taking other drugs that had potential antiviral activity. In this small subgroup, 8 people in the hydroxychloroquine group reached symptom alleviation in the second week while only one did in the control group. This was statistically significant at just a sliver under P=0.05.
The relevance of this subgroup analysis is doubtful. As the authors noted, none of the drugs they considered potentially antiviral (such as lopinavir-ritonavir, arbidol, oseltamivir, virazole, entecavir, ganciclovir and/or interferon-alpha) have any evidence yet for their efficacy in the context of COVID-19, and lopinavir-ritonavir already has an RCT showing it is not effective.
More to the point, the authors made 14 subgroup comparisons for symptom alleviation in the second week and the same 14 subgroup comparisons for viral clearance. That's 28 comparisons, one reaching statistical significance. Statistical significance at p<0.05 by definition means that if there were no effect at all, you would expect one out of 20 tests to reach significance just on random chance alone.
That is exactly what the authors found.
Although these results are perfectly consistent with complete random chance and no effect at all of the drug, they claimed that “adding hydroxychloroquine to the current standard-of-care in patients with COVID-19 does not increase virus response but accelerate[s] the alleviation of clinical symptoms.” This conclusion is dubious and contradicts their own pre-planned analysis of symptom alleviation as a secondary endpoint.
An Effect on Inflammation?
The authors didn't examine the erythrocyte sedimentation rate, IL-6, or TNF-alpha as planned because these measurements were not available for a large enough number of patients.
However, they did have data for CRP and the lymphocyte count.
Severe COVID-19 cases are associated with elevated CRP, often above 40 mg/L, and low lymphocyte counts. As I noted in the elderberry post, low lymphocyte counts in COVID-19 are a major predictor of severity and death.
CRP declined by 7 mg/L in the hydroxychloroquine group and 2.7 mg/L in the control group. The difference in the decrease was statistically significant at P=0.045.
The absolute lymphocyte count increased 62 per microliter in the hydroxychloroquine group and 8 per microliter in the control group. With normal lymphocyte counts between 1000 and 4800 per microliter, these seem meaningless. The P value was 0.547, meaning there would be a 55% chance of observing this difference if there were no effect of the drug.
Unfortunately, the authors do not report the absolute concentrations of CRP or lymphocytes. They only report the change from baseline.
Whenever I see a paper that only reports change from baseline, I assume the authors are hiding behind bad data and trying to cover up a statistical artifact like regression to the mean. Regression to the mean is the tendency for a randomly high value to come down, and a randomly low value to go up. If the baseline CRP in the hydroxychloroquine group was 50 and was 45 in the control group, then a 7-point decline in the hydroxychloroquine group and a 3-point decline in the control group would bring both groups to 43, an identical level. You would expect something like that from regression to the mean.
I wrote a post explaining this nine years ago, How a Study Can Show Something to Be True When It’s Completely False — Regression to the Mean.
The appropriate analysis for CRP would have been to show that the concentration of CRP at the end of the trial was lower in one group than the other. They did not report that data, so the finding should be disregarded.
They claimed that their study showed that “adding hydroxychloroquine to the current standard-of-care in patients with COVID-19 does not increase virus response but accelerate[s] the alleviation of clinical symptoms, possibly through anti-inflammatory properties and recovery of lymphopenia,” but they didn't show acceleration of the alleviation of clinical symptoms or improvements in CRP (inflammatory properties) or lymphocyte counts (lymphopenia).
Since hydroxychloroquine is an immunosupressant used to treat lupus and rheumatoid arthritis, it wouldn't be terribly surprising if it were able to calm CRP, recover the lymphocytes, and perhaps protect against the cytokine storm that leads to severe respiratory problems and death. In addition to the lack of compelling data in this study, however, the second preprint released yesterday casts further doubt on this hypothesis.
The Second Study: No Effect in Severe Cases
The second preprint released yesterday was appropriately titled, No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement.”
This was not a randomized controlled trial. Instead, they collected data from routine care to “emulate” a trial.
All electronic health records from March 17-31 of patients in four French medical centers used for COVID-19 pneumonia were searched for patients between the ages of 18-80 who had PCR-confirmed COVID-19 and required supplemental oxygen.
They excluded any patients under dialysis or with any other contraindication for hydroxychloroquine, anyone using hydroxychloroquine prior to admission, anyone treated with another experimental COVID-19 drug within 48 hours of admission, and anyone with organ failure or acute respiratory distress syndrome (ARDS) at admission. Patients were also excluded if they had been discharge from ICU to standard care or if at admission they had made the decision to not get treated at admission or expressed opposition to their data being collected.
They compared patients who received hydroxychloroquine at 600 mg per day starting within the first 48 h after admission to those who did not receive any of the drug, over the course of seven days.
Their primary outcome was the number of people who were either transferred to ICU or died from any cause within 7 days.
Of 181 eligible patients, 84 had received hydroxychloroquine within 48 hours of admission and 97 did not.
In the primary endpoint, 20.5% of those using hydroxychloroquine and 22.1% of those in the control group transferred to ICU or died.
3 patients in the hydroxychloroquine-treated group and 4 in the control group died.
In addition, 27.7% of the hydroxychloroquine-treated patients and 24.1% of the controls developed ARDS.
The numbers of deaths are too small to be meaningful. The percentages in the ICU/died and ARDS comparisons are almost identical (ARDS looks slightly better for the controls, while ICU/died looks slightly better for hydroxychloroquine) and not statistically significant.
The title phrase “no evidence of clinical efficacy of hydroxychloroquine” was appropriate.
Since inflammation plays a major role in the progression of severe cases to ARDS, critical care, and death, this study suggests that the immunosuppressive activity of hydroxychloroquine is unlikely to be of benefit in suppressing the COVID-19 cytokine storm.
Side Effects and Safety
In the RCT, 21% (30 patients) in the hydroxychloroquine group and only 8.8% (7 patients) in the control group reported adverse effects. The most common adverse effect was diarrhea. Two patients in the hydroxychloroquine group and zero controls progressed to severe COVID-19 symptoms. The drug was discontinued in one patient due to blurred vision, and the dose was adjusted downward in another patient who reported thirst as an adverse effect.
In the non-randomized French study, 9.5% of patients taking hydroxychloroquine develoepd abnormalities in their heart rhythm that required them to be taken off the medication according to French national guidelines. One developed atrioventricular block and one developed left bundle branch block, both of which are impairments in the ability of electrical signals to travel through the heart and keep it beating properly.
When comparing the safety profile in the two studies, the side effects seem to be more concerning in people with severe COVID-19. This further questions the possibility that the immunosuppressive properties of hydroxychloroquine could be used to counter the dangerous inflammation of the cytokine storm in severe cases.
Hydroxychloroquine in Context
Three other issues of this newsletter have been devoted to chloroquine and hydroxychloroquine:
Chloroquine and hydroxychloroquine, used as anti-malarial drugs, are essentially cellular poisons that alkalinize all of the acidic compartments of the cell. This has antiviral properties, because many viruses depend on acidity to enter the cell. It also has immunosuppressive properties because antibodies and other parts of the immune system depend on the acidity of certain parts of the cell to be produced properly. However, this hurts the ability to take anything into the cell through a process called endocytosis, it hurts the digestive functions of cells, and it hurts the processing of thousands of proteins. It's like carpet bombing on the level of acid-base balance. It's an extremely blunt tool.
Hydroxychloroquine's immunosuppressive properties make it useful for inflammatory disorders such as lupus and rheumatoid arthritis.
Chloroquine, however, has a terrible track record for antiviral properties. In vitro, meaning in a test tube, it is antiviral toward the flu, dengue, and chikungunya. But it has failed to prove beneficial in humans for the flu and dengue, and it acted as a proviral in multiple animal models for chikungunya.
These drugs are cellular poisons with both antiviral and immunosuppressive properties. In COVID-19, which will win out?
So far it looks like neither. Perhaps it's putting patients in a tug-of-war that is being pulled equally from both ends.
As data comes in, particularly RCTs, it looks more and more like the drug does very little if anything.
Stay safe,
Chris
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I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
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*Footnotes
* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.