Chloroquine and other drugs for COVID-19

Chloroquine (phosphate), one brand name Nivaquine, is a very old anti-malarial drug used since the 1930’s, now de-emphasised for malaria because of resistant strains, but remaining in use for many other purposes e.g. rheumatoid arthritis, polio, HIV and systemic lupus erythamatosus (aka "lupus" or SLE). It is a derivative of quinine, a natural product, before WWII the standard treatment for malaria and still used in tonic water as a flavouring. 

Having been used for decades, its tolerance and contra-indications are well known and in many parts of the world it is still routinely available, especially where malaria remains endemic, without prescription. (France only required a prescription from January his year). A strip of 5 tablets can be bought in India for Rs12 i.e. about 1.5p. There is absolutely no money in it for Big Pharma. 

It tastes unbelievably bitter (I was allowed a small shot of sherry as a child when taking it as a malaria prophylactic), overdoses will risk liver damage and it can change heart rhythms, but it did what it said in the packet, i.e. prevent, and treat, malaria. 

The relative hydroxychloroquine (sulphate) (typical brand Plaquenil) is newer and better tolerated; likely to be the drug of choice if it is truly successful for Covid-19. 

Shorthands for these notes: HCQ for hydroxychloroquine (as sulphate), CQ for chloroquine (as phosphate).

Azithromycin (shorthand AZM, typical brand name Zithromax or Z-pak) is an antibiotic similarly well-established for infections like traveler's “runs” and chlamydia. It also has known anti-viral action against larger viruses such as Ebola and Zika. Given to patients in Marseilles with the intention of preventing bacterial “super-infection” i.e. infection “on top of” the C19, they conjectured a synergistic effect with chloroquine against C19; in their first clinical trial, some but not all patients were cleared of the virus with HCQ alone; all were cleared with the combination. 

Also long-established, with tolerance and contra-indications well-known; it is obtainable by mail-order subject to consent from a GP.

Zinc (as a simple chemical compound) is also of relevance, is a component of the Marseilles protocol; and is widely available as a “nutraceutical” or “health food supplement”. You can get zinc gluconate tablets from Holland and Barrett, and it is added to some Vitamin C supplements available at retail outlets.

The excitement over these drugs is that they already exist. Their tolerances and contra-indications are very well-known. The only question is if they are effective against Covid-19 infections, and in particular if the HCQ+AZM combination is yet more so. The Marseilles group clearly have had significant success, are now using it routinely, as are doctors in New York state; the US FDA and French authorities have now issued emergency licensing for their use in Covid-19 and evidence is mounting from doctors across the world, when confronted with the necessity of "battlefield medicine", that the combination is effective, particularly when taken early in the infection (a recent report from Brazil says Days 2-4 of symptoms)

 The Marseille team of Prof Didier Raoult noted chloroquine as a potential broad-spectrum antiviral, of negligible cost, and extremely well-known tolerance in a short Letter on 11 February with a terse summary of the possible modes of action.

Prof Raoult is founder and director of l'Institut Hospital-Universitaire Mediterannee Infection (IHI-MI) and one of the world's leading experts in infectious diseases - some sites rate the "World #1" based on research publications. 

He is an advocate of "drug repurposing" i.e. finding new uses for established medicines, which are well out of patent (so no profit motive for anyone), cheap, and with established safety and tolerance. This certainly applies to chloroquine, which has been known since 1934, and has negligible cost anywhere.

This letter proposed the use of CQ and HCQ against the SARS-CoV-2 virus.

This paper is rightly called a "Breakthrough". 

Cited by the Marseilles group on 11 February when available as pre-publication e-print; 

not actually published until 19 February 2020.  

From Chinese scientists at Qingdao. Multi-centre clinical trials in China were showed success against controls in treating COVID-19 pneumonia, in a group of over 100 patients.

By 14 March, the Marseilles group had tabulated the principal studies on the effectiveness of chloroquine against coronaviruses in vitro; and cited the Qingdao clinical trial paper (11 or 19 February), and noted from their own experience that effective concentrations of CQ could be reached with clinically tolerable doses.

The major advance in a clinical trial came with a study published on 16 March:

This paper compared three groups of patients (i) an untreated control group (16) (ii) a group treated with HCQ alone (14) (iii) a third group treated with HCQ plus azithromycin (AZM) (6 patients). Whilst a small patient number (36 patients) and not a randomized or double-blinded trial, the results were dramatic; after 6 days only 2/16 patients in the control group showed no remaining virus; 8/14 (57%) treated with HCQ were clear of virus by Day 6, and in the combination treatment group 6/6 (100%) were cured after 6 days. 

Figure 2 (is the graph above) 

Percentage of patients with PCR-positive nasopharyngeal samples from inclusion to day6 post-inclusion in COVID-19 patients treated with hydroxychloroquine only, in COVID-19 patients treated with hydroxychloroquine and azithomycin combination, and in COVID-19 control patients.

The addition of azithromycin was made to control bacterial “super-infection” (ie bacterial infection on top of the Covid-19 disease) but from these results the Marseilles group conjectured a synergistic effect of the two drugs in combination. 

AZM had been demonstrated as effective against Zika virus by the Marseilles group, and against Ebola by others. Its established use to treat chlamydia is likewise action against an obligate parasite (chlamydia trachomatis) that has to invade a host cell in order to reproduce. 

Anti-viral action is therefore not unexpected although it was not the principal reason for inclusion. (Again, statements on the lines of "this is an antibiotic, and cannot be expected to be effective against viruses", are wide of the mark).

Their summary:

We therefore recommend that COVID-19 patients be treated with hydroxychloroquine and azithromycin to cure their infection and to limit the transmission of the virus to other people in order to curb the spread of COVID-19 in the world. Further works are also warranted to determine if these compounds could be useful as chemoprophylaxis to prevent the transmission of the virus, especially for healthcare workers.

A video announcing the results was also released:

https://www.mediterranee-infection.com/coronavirus-diagnostiquons-et-traitons-premiers-resultats-pour-la-chloroquine/

Released on Twitter on 27 March, results showed  93% patients no longer contagious after 8 days; 97.5% of those tested had no virus cultured from lung samples after 5 days.

Figure 1 (above). SARS-CoV-2 PCR from nasopharyngeal samples overtime. Black bars: number of patients with available results, grey bars: number of patients with PCR Ct value <34, solid line: percentage of patients with PCR Ct value <34, dashed line: polynomial regression curve.

Conclusion: 

Given the urgent therapeutic need to manage this disease with effective and safe drugs and given the negligible cost of both hydroxychloroquine and azithromycin, we believe that other teams should urgently evaluate this therapeutic strategy both to avoid the spread of the disease and to treat patients before severe irreversible respiratory complications take hold