The most popular drug with doctors all over the world will seemingly now not even be allowed in the US for Covid related treatment:
HCQ No Longer Approved Even a Little for COVID-19
Molly Walker, MedPage
The FDA rescinded its emergency use authorization (EUA) of hydroxychloroquine (HCQ) to treat COVID-19 patients, citing concerns about efficacy and risks associated with its use, and saying the drug no longer meets the criteria for an EUA, the agency said on Monday.
Moreover, the FDA now says the benefits of the drug “no longer outweigh the potential risks,” citing the serious cardiac adverse events associated with the drug.
Comments underneath reveal just how contested this will be.
It’s a strange situation where patients in many poorer nations are being offered drugs that patients won’t be able to get in the richest nation in the world:
Substantial fractions of physicians treating Covid-19 patients in Europe and elsewhere report use of HCQ+AZ: 72% in Spain, 49% in Italy, 41% in Brazil, 39% in Mexico, 28% in France, 23% in the US, 17% in Germany, 16% in Canada, 13% in the UK (45), much of the non-US use in outpatients.
Yet strangely, despite the thousands of people using HCQ, there are not many (or any) ideal trials. Most are non-randomized, but the few that are, usually started too late, or are not combined with zinc or the right antibiotic.
A few weeks ago, a Yale expert made the case of why the US should be using HCQ as early as possible. He calculates that at the current death rate, by the time the results of the right trial is known 180,000 people will have died.” In this context, we cannot afford the luxury of perfect knowledge…”
Prof Harvey Risch insists HCQ needs to be tried in patients before they get to hospital
Harvey Risch is a Professor of Epidemiology at the Yale School of Public Health. He compares the two top treatments in the USA — the anti-malarial drug HCQ (Hydroxycholorquine) and the anti-Ebola drug — Remdesivir. In a 29 page review he concludes that with the US reopening, and 10,000 people dying each week, they don’t have time to wait for the randomized controlled trials — but that they urgently need a drug that can reduce the rate of hospitalization, and there is already enough data to warrant the use of HCQ + AZ (Azithromycin) and Zinc.
US officials are recommending Remdesivir but there is no randomized controlled trial on that yet either for outpatient use. Instead, it’s a newer drug with mainly lab and animal research. HCQ, on the other hand, is an old cheap drug with very low and well-known risks. It’s being used in poorer countries all over the world, and many doctors on the frontline are convinced it helps, even though there are not yet the proper studies to show whether it does or not.
There are five trials on the ClinicalTrials.gov database for HCQ and Az in the outpatient setting. Risch discusses all of them.
One French study is small, but shows a 50 fold benefit when started early, and only (!) a 25 fold benefit when waiting until it has progressed to the lower respiratory tract.There was a seven-fold benefit from taking the antibotic (AZ) at the same time. He works through all the criticisms below, pointing out that even though the study is small, the magnitude of the effect is so large, it is still obvious the combination is beneficial.
This point has been argued forcefully by the French doctors (20). The first study of HCQ+AZ (24) was controlled but not randomized or blinded, and involved 42 patients in Marseilles, France. This study showed a 50-fold benefit of HCQ+AZ vs standard-of-care, with P-value=.0007. In the study, six patients progressed, stopped medication use and left the trial before the day-6 planned outcome measure of swabsampled nasopharyngeal viral clearance. Reanalysis of the raw study data elsewhere (25) and by myself shows that including these six patients does not much change the 50-fold benefit. What does change the magnitude of benefit is presentation with asymptomatic or upper respiratory tract infection, vs lower respiratory-tract infection, the latter cutting the efficacy in half, 25-fold vs standard-of-care. This shows that the sooner these medications are used, the better their effectiveness, as would be expected for viral early respiratory disease. The average start date of medication use in this study was day-4 of symptoms. This study has been criticized on various grounds that are not germane to the science, but the most salient criticism is the lack of randomization into the control and treatment groups. This is a valid general scientific criticism, but does not represent epidemiologic experience in this instance. If the study had shown a 2-fold or perhaps 3-fold benefit, that magnitude of result could be postulated to have occurred because of subject-group differences from lack of randomization. However, the 25-fold or 50-fold benefit found in this study is not amenable to lack of randomization as the sole reason for such a huge magnitude of benefit. Further, the study showed a significant, 7-fold benefit of taking HCQ+AZ over HCQ alone, P-value=.035, which cannot be explained by differential characteristics of the controls, since it compares one treatment group to the other, and the treated subjects who received AZ had more progressed pneumonia than the treated subjects receiving HCQ alone, which should otherwise have led to worse outcomes. The study has also been described as “small,” but that criticism only applies to studies not finding statistical significance… page 8 ,9
A second study of the Marseilles group (27) involved 1061 patients tested positive for SARS-CoV-2 and treated with HCQ+AZ for at least 3 days and followed for at least 9 days. The authors state “No cardiac toxicity was observed.” Good clinical outcome and virological cure were seen in 973 patients (92%). Five patients died, and the remainder were in various stages of recovery.
In Brazil, 412 patients were treated with HCQ plus deoxycycline (a different antibiotic). Those treated before day 7 had about one third the chance of ending up in hospital, as those did who started treatment later. (29)
Adding zinc to the combination cut mortality in half again:
HCQ+AZ has been standard-of-care treatment at the four New York University hospitals, where a recent study showed that adding zinc sulfate to this regimen significantly cut both intubation and mortality risks by almost half (46).
As far as side effects go, the FDA FAERS database (34) contains 1064 adverse events for HCQ, including 200 deaths, but this goes back the full 50 years of use involving millions of patients. Many of these patients were not using HCQ for five days (as Covid patients are) they were using it for months on end.
Doctors are very well aware of the long QT problem with hearts, and know which people HCQ is not suited too.
For those interested in this debate, his conclusions make for interesting reading. See the PDF.
h/t Ian B,David B, Lance, Lucky.
REFERENCES (In the Prof Reisch of Yale paper).
Risch, H. (2020) American Journal of Epidemiology, kwaa093, https://doi.org/10.1093/aje/kwaa093 PDF
(20) Guerin V, Lardenois T, Levy P, et al. Covid-19: Etude rétrospective chez 88 sujets avec 3 approches thérapeutiques différentes. April 30, 2020. .
(24) Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID‐ 19: results of an open‐ label non‐ randomized clinical trial. Int J Antimicrob Agent 2020 Mar 17.
(27) Million M, Lagier J-C, Gautret P, et al. Early treatment of 1061 COVID-19 patients with hydroxychloroquine and azithromycin, Marseille, France. April 20, 2020.
(29) Barbosa Esper R, Souza da Silva R, Oikawa FTC, et al. Empirical treatment with hydroxychloroquine and azithromycin for suspected cases of COVID-19 followed-up by telemedicine. April 15, 2020.
(45) Sermo. Breaking Results: Sermo’s COVID-19 Real Time Barometer Study. Wave I. .
(46) Carlucci PM, Ahuja T, Petrilli C, et al. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. Preprints. 2020. (https://doi.org/10.1101/2020.05.02.20080036). Accessed May 8, 2020.
(47) Derwand R, Scholz M. Does zinc supplementation enhance the clinical efficacy of chloroquine/hydroxychloroquine to win todays battle against COVID-19? Med Hypotheses 2020, in press. (https://doi.org/10.1016/j.mehy.2020.109815). Accessed May 7, 2020.