The French study on treatment of COVID-19 with azithromycin/hydroxychloroquine: impressive, but no controls. Caution is advisable.

(photo courtesy of pixabay.com and David Mark)

Research that could support the compassionate use of chloroquine and azithromycin based on basic, preclinical, and clinical data is sorely lacking.  A preprint literature search I found on Biorxiv located 19 studies that relate to this issue.  Further clinical (experiments on humans) research will be difficult during this pandemic.

The clinical study that matters is this (a pdr version from IHU-Méditerranée Infection, Marseille, France, published on March 20).  It included eighty patients, treating them all with hydroxychloroquine 200 mg three times a day and azithromycin 500 mg once followed by 250 mg daily for five days (also known as “Z-pack”– a prepackaged unit with seven azithromycin 250 mg tablets).  There was no control group at all, and the authors relied on published data from other studies for comparison.

Patients in this study had a dramatically shortened period of virus shedding from their noses and throats: 83% had no virus detected by PCR (polymerase chain reaction) after day seven.  Historical controls from another study of 191 patients in Wuhan were found to have a median duration of viral shedding of 20 days.  One of the French patients died, but 54 died in Wuhan.  This is impressive, to say the least, but there are many caveats.

For example, were patients pre-selected inadvertently?  The 80 Marseilles patients all had mild to moderate disease at the beginning of treatment, except for one 86 year-old who went on to die.  The 191 Wuhan patients were all consecutive admissions, many with severe disease.  Treatments for the Wuhan patients were not described in the abstract.  Quality of care was clearly better for the Marseilles patients, who were all isolated in separate isolation rooms.  For these reasons, it would have been more appropriate to select controls from the Marseilles hospital; perhaps the predisposition to treat all patients with the drug combination there made this impossible.

There is little reason for not treating hospitalized patients with this drug combination when it is available.  Outpatients are another matter.  Hydroxychloroquine is in short supply at local outpatient pharmacies, although azithromycin is readily available (in fact, over a billion courses of “Z-pack” or its generic equivalent have been delivered, according to the Marseilles study).

This study is solely of hospital treatment at a well-equipped respiratory isolation medical center not under immediate threat of being overwhelmed with sick people.  It was compared with treatment at a public hospital inundated with sick people.  The results were used to justify early discharge for these patients in order to free up beds expected to be needed for newly admitted individuals.  This is reasonable given that viral shedding, and therefore infectiousness, was stopped in about a week.  Did the difference in hospital setting make a difference in the results?  We don’t know, given that the Marseilles researchers didn’t attempt to collect any control patients at their own hospital; unfortunately, this is a key factor in case/control studies.

The authors of the Marseilles study also noted that a Chinese study of chloroquine treatment had negative results with 30 patients.  Whether azithromycin made the difference is difficult to ascertain.  Azithromycin by itself shows some signs of effectiveness against rhinoviruses but it is, like hydroxychloroquine, not approved for antiviral use.

There will be great difficulties in performing further research during a pandemic.  We hope that those responsible for doing these studies will continue to accumulate patient data in a form that can be shared with other researchers.  Part of these efforts will include obtaining informed consent from patients to share their data in a de-identified (with names and other identifying information removed) form.

I have to stop now to try and get some sleep.  It is five AM here on the West Coast.   I couldn’t sleep thinking about the post that I tried to write last night at nine PM that simply disappeared after I had put down 684 words.  I tried to use Ctrl A, Ctrl C to copy those words, but my free WordPress word processor appeared to seize up and everything vanished.  I was so frustrated that I gave up and went back to watching TCM, but after four hours of sleep I am back (not for long, I hope).  The photo I selected for this post reflects my frustration and isolation.