Hydroxychloroquine, chloroquine and Zithromax

May 26, 2020

Periodically, we scour PubMed for newly published studies that are of interest to the naturopathic profession.  Some of these studies will then be reviewed in the Natural Medicine Journal (NMJ).

As the matter topmost on our minds, my initial search this morning was for new studies related to “covid-19.”  That search reveals a list of over 8,000 citations.  Since NMJ will only review studies that are human clinical trials, I refined my search using those limits.   That reduced the list of relevant studies down to eleven.  

Of those eleven studies, six tested whether hydroxychloroquine or chloroquine offered any benefit in treating this disease.  

Tang et al, published in the British Medical Journal (BMJ) May 14, 2020 is the most recent publication.  6 government designated covid-19 treatment centers in China, 11 to 29 Researchers tracked 150 patients admitted to more than a dozen different Chinese hospitals in mid-February 2020.  Half received hydroxychloroquine plus standard of care and half only standard care.  Though side effects were worse in the patients receiving the drug, the drug made no significant impact on recovery.[i]

A second Chinese clinical trial was published May 25, 2020.  Chen et al enrolled Covid-19 patients and split them into experimental and control groups.  Those in the experimental group received 400 mg/day of hydroxychloroquine a day for 5 days. There was no significant difference in how many patients had recovered by day 7 between groups.[ii]

JAMA has twice published results from a clinical trial done by Mayla Borba et al, first on April Fool’s Day and on April 24, 2020.  They tracked patients hospitalized with severe covid-19 infections the last week of March through April 5 in their hospital in the Brazilian Amazon.

Patients were given either high dose chloroquine (600 mg twice/day) or low dose (450 mg twice on day 1 and then once/day for 4 additional days).  Mortality varied with dosage.  By day 13 of the study 39% of the patients in the high dose group had died while only 15% of those taking the lower dose had died.  [iii] [iv]

 An earlier clinical trial by Molina et al, published online March 30, 2020, is not shy about its results: this is the title: 

“No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection.” [v]

Their study was done in France in response to the amazing results reported in the earlier preprint paper by their compatriots in Marseille.  In that earliest study on hydroxychloroquine, Gautret et al reported a 100% viral clearance in 6 patients after 5 and 6 days of the combination of hydroxychloroquine and azithromycin. This rate of viral clearance was lower with hydroxychloroquine alone (57.1%) and was only 12.5% in patients who did not receive hydroxychloroquine.[vi]

Molina and colleagues considered Gautret’s results and thought that “… such a rapid and full viral clearance was quite unexpected…”  They ran a prospective study of 11 consecutive patients dosing hydroxychloroquine (600 mg/day for ten days) and azithromycin (standard five-day course: 500 mg day one and 250 mg days 2-5), basically copying Gautret’s claimed treatment. Their results, well as mentioned, the title of their paper sums them up.

Gautret’s research was conducted under the supervision of Didier Raoult, the scientist who founded and directs the research hospital known as the Institut Hospitalo-Universitaire Méditerranée Infection.  Raoult is a rare sort of individual and has an international reputation for both brilliance and eccentricity, so much so that the New York Times ran a feature article about him just a few Sundays back.  [vii]. Most reports describe Raoult as the lead author of this study.

On April 3, 2020, the International Journal of Antimicrobial Agents (IJAA), published a notice that Gautret’s original article did not meet their expected standard and would be reexamined.  

On April 8, 2020, MedScape published a review of that situation written by the staff of Retraction Watch, a group that does just that, watches for published papers that are retracted by the scientific journals that published them to make sure the scientific community is aware that the information is no longer considered valid. 

Noting that the Gautret-Raoult paper, “… appears to have triggered the Trump administration’s obsession with hydroxychloroquine as a treatment for infection with the novel coronavirus…” they suggest that. IJAA’s expression might be too little too late;

“Of course, the horse has left the proverbial barn on this one. An untold number of patients have been receiving hydroxychloroquine, as well as chloroquine, for COVID-19 infection, thanks in large part to cheerleading for the drugs from President Trump.

 “Although a certain amount of haste is to be expected in a medical crisis, and sometimes spitballing may be a viable option, the use of poorly investigated therapies is hardly risk free. In this case, not only do the drugs carry significant side effects, but they are critical treatments for people with lupus and rheumatoid arthritis — patients who now have to hope that they can still get access to medications that are keeping them alive.” [viii]

The largest clinical trial to date on using hydroxychloroquine was published last Friday, May 22, 2020 in the Lancet.  Mandeep Mehra et al examined data from 96,000 patients hospitalized with Covid-19 infection who received hydroxychloroquine and report that they actually had a significantly higher risk of death compared to those who did not receive this treatment.  Let me pull the important numbers from the paper:

96,032 patients; their mean age was 53.8 years, 46·3% women. Of these, 14,888 patients received one of these experimental drugs; 1,868 received chloroquine, 3,783 received chloroquine with a macrolide (the family name for Zithromax), 3,016 received hydroxychloroquine, and 6,221 received hydroxychloroquine with a macrolide, leaving 81,144 patients to serve as a control group. 10,698 (11.1%) of the patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), the control group who received none of these experimental treatments had the lowest mortality rate; 9.3% of them died. 18% of the patients who received hydroxychloroquine died. Combining hydroxychloroquine with a macrolide (Zithromax) increased mortality to 23.8%.  Similar higher death rates were seen with chloroquine alone (16.4%) and chloroquine with macrolide (22.2%).  Those receiving any of these experimental drug combinations were more likely to experience ventricular arrhythmia while in the hospital, the highest was for those receiving hydroxychloroquine and macrolide (8.1%). [ix]

This study seems to be a very strong rebuttal of any promised miracle cure from these drugs either alone or in combination.  Especially when considered in light of how weak Gautret’s original trial was, and then the subsequent studies that have refuted those findings.

Many have been skeptical of the idea that a drug used to treat malaria would have any effect against a virus from the moment Gautret’s initial report appeared as a preprint version last winter, and their skepticism has only grown with each subsequent publication.  

One may have assumed that other research on other potential treatments was still moving forward.  That doesn’t seem to be the case.  The other clinical trials related to Covid-19 published to date reveal little of great interest.  Wei et al have had a clinical trial published on using the internet to treat Covid-19 caused anxiety and depression.[x] (Which actually is of enough interest that NMJ will likely review it.)   Liu et al suggest progressive muscle relaxation to improve sleep for those worried about Covid-19. [xi]  Another (or the same?) Liu has a paper out on respiratory rehab treatments in older patients recovering from Covid-19. [xii]  Huang et al describe how to best take images to diagnose Covid-19 caused pneumonia.[xiii]  The remaining clinical trials published on Covid-19 this year, as mentioned, have all been related to hydroxychloroquine and chloroquine.  

There are lists of potential therapies put forward as potential treatments against Covid-19, many with strong theoretical arguments and/or in vitro research in support yet still needing to be tested on humans.    There is no reason to put any further time or effort into attempting to prove that these drug combinations are useful. Time, energy and money should be invested in finding things that work.  One must question the motives of anyone who, at this point in time, promotes use of these drugs against this particular disease.

[i] Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirusdisease 2019: open label, randomised controlled trial. BMJ. 2020 May 14;369:m1849. 

[ii] Chen J, Liu D, Liu L, et al.  [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020 May 25;49(2):215-219.

[iii] Borba MGS, Val FFA, Sampaio VS, et al.  Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory SyndromeCoronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open. 2020 Apr 1;3(4):e208857.

[iv] Borba MGS, Val FFA, Sampaio VS, et al Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory SyndromeCoronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open. 2020 Apr 24;3(4):e208857. 

[v] Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020 Jun;50(4):384. 

[vi] Gautret P., Lagier J.C., Parola P. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomised clinical trial. Int J Antimicrob Agents. 2020 

[vii]  Scott Sayare. “He Was a Science Star. Then He Promoted a Questionable Cure for Covid-19.

The man behind Trump’s favorite unproven treatment has made a great career assailing orthodoxy. His claim of a 100 percent cure rate shocked scientists around the world.”

New York Times. May 12, 2020

[viii] https://retractionwatch.com/2020/04/06/hydroxychlorine-covid-19-study-did-not-meet-publishing-societys-expected-standard/ 

[ix]Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. http://www.thelancet.com Published online May 22, 2020.


[x] Wei N, Huang BC, Lu SJ, et al.  Efficacy of internet-based integrated intervention on depression and anxiety symptoms in patients with COVID-19..J Zhejiang Univ Sci B. 2020 May;21(5):400-404. doi: 10.1631/jzus.B2010013. Epub 2020 Apr 1.

[xi] Liu K, Chen Y, Wu D, Lin R, Wang Z, Pan L. Effects of progressive muscle relaxation on anxiety and sleep quality in patients with COVID-19. Complement Ther Clin Pract. 2020 May;39:101132. 

[xii] Liu K, Zhang W, Yang Y, Zhang J, Li Y, Chen Y Respiratory rehabilitation in elderly patients with COVID-19: A randomized controlled study. Complement Ther Clin Pract. 2020 May;39:101166. doi: 10.1016/j.ctcp.2020.101166. Epub 2020 Apr 1.

[xiii] Huang Z, Zhao S, Xu L, et al.  Imaging features and mechanisms of novel coronavirus pneumonia (COVID-19): Study Protocol Clinical Trial (SPIRIT Compliant). Medicine (Baltimore). 2020 Apr;99(16):e19900.