Hydroxychloroquine drug tests for COVID-19: media manipulations?
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A few months ago I published my blog on the COVID-19 situation and I mentioned hydroxychloroquine and Remdesivir as -strongly debated- possible drugs. (Oops, I wrote there "hydrochloroquine".)
In fact, it may be said that a media war was going on about hydroxychloroquine. For a while I didn't have an opinion about it (if anything, I was skeptical), but a slow-motion film of events give an idea of what was -and still is- going on.
As this blog post has become much longer than originally intended, I'll start with a little comparative summary.
- is cheap, and is widely available
- is taken orally
- is known to increase risk of heart failure; when that is carefully taken in account there is little risk
- seems to reduce the death toll if given soon after infection or immediately upon the first symptoms
- may still have a beneficial effect even if only given from the start of hospitalization (unsure).
For clarification of the above, together with my observation about the hydroxychloroquine saga, see here below.
- is expensive, with huge financial interest by the company Gilead
- has to be injected
- is said to significantly increase the risk of renal failure and possibly liver damage
- apparently reduces hospital time
- apparently does not save lives
Obviously, neither of the two is a miracle treatment for COVID-19 patients.
Concerning Remdesivir, I didn't spend much time on that, my opinion is based on the following:
- The Indian government warned about possible liver damage
- a very small clinical study reported worrying results : "four of the five patients experienced major side effects while on remdesivir treatment: two suffered acuterenal injury and two had a maculopapular rash with cytolytichepatitis. Both kidney failure events could have been related either to remdesivir or to the SARS-CoV-2 infection." Maybe a beneficial effect against COVID and an increased risk of organ failure compensate each other?
In contrast, the press now declares hydroxychloroquine dead and buried. In many western countries hydroxychloroquine has not been approved for treating Covid-19, while Remdesivir has been approved. How can that be?
The hydroxychloroquine saga
Here follows a sketch of my observations; I'll abbreviate hydroxychloroquine to HCQ.
Different observational studies reported completely inconsistent results, according to some the drug was very effective while according to others it didn't help at all. Within months, proponents of the drug such as Prof. Raoult of France claimed that it helps, but that it should be given early.
It makes sense to me that an antiviral drug may be most effective by slowing down virus multiplication before there are many virus particles, thus giving the body time to set up its immune system defence. That also resonates with reports according to which women tend to be less affected than men because women have a faster immune response.
As I'm just an informed bystander, I'm not supposed to know as much about this as a health minister is supposed to know. It was therefore shocking for me to hear on the news that the French Health Ministry officially prohibited the utilization of HCQ as recommended by Raoult, and to allow the treatment only for late stage Covid-19 patients.
"When damage to the lungs is too important, and patients arrive for reanimation, they practically do not harbor viruses in their bodies any more. It’s too late to treat them with chloroquine. Are these the only cases – the very serious cases – that will be treated with chloroquine under the new directive by [French Health Minister] Veran?” If so, he added ironically, “then they will be able to say with scientific certainty that chloroquine does not work".
I saw no massive street protests on TV and the French health minister is not in jail - in fact, he's still in charge!
In March finally a double blind study by dr. Boulware was published in the New England Journal of Medicine.
At the time I didn't pay attention to it, and Boulware simply concluded that "hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure." (Ok so it's not a prophylaxis, well too bad). But on hindsight, it's worthy of a second look.
A first criticism by French press can be found in Francesoir: They notice that treatment within the first two days of exposure seems to have a significant benefit; this is however not shown on the picture nor was it mentioned in the conclusion. And they point out that the main researcher dr. Boulware had a research grant from Gilead Sciences which tries to market Remdesivir instead of HCQ.
Later a complete re-analysis by Watanabe, a statistician, was pre-published. His conclusion - at 99% confidence level(!) - was that
it can significantly reduce the relative proportion of symptomatic patients if used [starting] from 0 to 2 days after exposure to the virus
Our results show that the time elapsed between infection and the beginning of treatment is crucial for the efficacy of hydroxychloroquine as a treatment to Covid-19. [...] This might explain why many studies have found no statistical evidence of effectiveness of hydroxychloroquine treatment when used in hospitalized patients as most of this more severe cases had probably started treatment long after 4 days from their exposure to the virus.
In May appeared the massive observational study with data from 96,032 patients that was published in the prestigious journal the Lancet. It was like a bomb shell exploding, you probably heard of it as the press proclaimed that the study showed that HCQ is dangerous.
Anyone who went to the tropics in the past knows that chloroquine, and even more so HCQ, are (or were) relatively safe over-the-counter drugs that people take for many weeks just in case a malaria mosquito would bite them. Doctors know the risk groups that should not receive the drug, in particular heart patients. Nevertheless newspapers, radio and TV uncritically cited:
Our data has very convincingly shown that across the world in a real-world population that this drug combination, whichever way you slice it or dice it, does not show any evidence of benefit, and in fact, is immutably showing a signal of grave harm - dr. Mehra
Moreover the World Health Organization hastily announced the world-wide cessation of clinical trials with HCQ. Again I was stunned - how could they take such a crucial decision based on one single article that even stressed, to the contrary, that "urgent confirmation from randomized clinical trials is needed"?
But then it became a big scandal because it turned out that the data was flawed to say the least, with the data coming from a tiny and not-so-serious looking company called Surgisphere.
surgisphere.com has already disappeared from the web, and if you try to see it on the WayBack machine of https://archive.org/ then you're in for a bad surprise. However you can still find snapshots on http://archive.is/surgisphere.com.
Then the group of dr. Boulware published another interesting paper as follow-up of their earlier study, in which they intended to compare hospitalizations and deaths between patients with and without HCQ immediately after onset of symptoms (that is, NOT immediately after infection).
They found that with placebo 8 patients were hospitalized for COVID-19 and one of them died, while with HCQ 4 patients were hospitalized and one died without hospitalization. As they realized early on that they probably wouldn't be able to achieve sufficient numbers to reach a conclusion, they looked at severity instead (without any consideration of hospitalizations). Although the group with HCQ did slightly better symptom-wise and had less hospitalizations, they simply concluded that "Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19".
Further, an article by Gautret et al of the group of Prof. Raoult created a lot of criticism. Its conclusion was that
hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
That sounded great, but quickly it was heavily criticized:
[Of] 26 in the treated group [...] six were excluded [...]: three were transferred to the ICU, one died, and two terminated treatment or were discharged.[...] it is noteworthy that 4/26 treated patients deteriorated and 0/16 control patients, which emphasises that the groups were different.
Indeed, excluding intensive care admissions and even a death from consideration doesn't sound very convincing to say the least! That strengthened my skepticism at the time. Retrospectively I think that the authors should maybe have explained their reasoning better. As a matter of fact, the patient that died was apparently virus-free on day 2 and died the next day; thus it appears that treatment was started too late in that case.
Very recently two more studies came to my attention, again delaying this blog post. The first is an impressive statistical meta analysis of many studies: Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis by Fiolet et al.
This is a study without apparent commercial ties and they did a big effort to select reliable information from the literature and to correct for possible bias. Their conclusion:
this meta-analysis clearly shows that hydroxychloroquine alone is not effective for the treatment of COVID-19 patients and that the combination of hydroxychloroquine and azithromycin increases the risk of mortality.
The higher risk of mortality may well be due to insufficient care in some hospitals with excluding risk groups and too high drug dosages; apparently they did not analyze the effect of higher or lower drug dosages. Moreover they stated "As is usually done, this meta-analysis was based on aggregated data, without access to original patient data." While the authors cannot blamed for that, it strongly reduces the value of such studies in my opinion.
I searched for but did not find subgroup analyses for pertinent factors such as drug dosage and time of start of drug administration - by throwing different studies into the same bin and mixing them, the statistical value increases but good treatments may be hidden as they average out with bad treatments.
Further, only one study on non-hospitalized patients was included: the second one of the group of Boulware, having one death with placebo and HCQ each. As that's statistically not very meaningful, their conclusion is much too categorical.
On a side note, a studies overview by Prof. Raoult is enlightening (although by now he's obviously far from neutral): he noticed that in line with the expected averaging out of good and bad treatments, "Big Data" articles (column 1) tend to lead to negative conclusions (column 3). Also the conflict of interest column is interesting (for info: the arched lines are randomized studies).
Back to the meta-study. I find it striking that the article ends with:
Our results suggest that there is no need for further studies evaluating these molecules, and the European DisCoveRy clinical trial or the WHO international Solidarity clinical trial have already discontinued treatment arms using hydroxychloroquine.
That's not quite right.
We already saw that HCQ almost certainly helps when given immediately after infection, and probably even when only started with the appearance of the first symptoms. Their link to the Solidarity trial points to the statement that it found "little or no reduction in the mortality of hospitalized COVID-19 patients", but that this "does not affect the possible evaluation in other studies of hydroxychloroquine [...] in non-hospitalized patients or as pre- or post-exposure prophylaxis for COVID-19".
Further, their link to the DisCoveRy trial points to a press statement that only mentions it in passing. However I found the relevant press statement, according to which that trial was suspended because of the aforementioned (and fake) Lancet study. I suspect that without that fake study, they would not have suspended it.
Coincidentally I noticed that another press report from the same institute does confirm that great care is required when combining azithromycin and HCQ as historically, “potentially fatal acute cardiac proarrhythmic effects have been described primarily with azithromycin but also with hydroxychloroquine" and "their combination gave a stronger signal."
One of the meta study's authors took part in a fake publication in order to show how some journals just accept anything. However, the topic of that fake paper indirectly ridicules a very erroneous prevision of dr. Raoult; that may be an indication of a combined anti-Raoult and anti-HCQ bias, see the story here.
Despite the apparent anti-HCQ confirmation bias of the authors, it looked quite convincing to me that HCQ may not be not useful when only taken after hospitalization. But then, at the last moment, I stumbled on a very big study that is still "in press": Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study.
That study considers 3451 patients in the whole of Italy. Overall, slightly lower doses of HCQ are used in Italy. They found in that observational study that:
HCQ use was associated with a 30% lower risk of death in COVID-19 hospitalized patients.
They also remarked (in this hospital environment) that "the anti-inflammatory potential of HCQ may have had more important role rather than its antiviral properties."
Funny enough, I didn't see or hear anything about that last study in the news. Coincidence?
Balancing the latest two studies, I now modified my "likely not" back in to a "may have"!
Comments and suggestions are welcome!
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