Can a Hydroxychloroquine/Azithromycin Combination End this Coronavirus Nightmare?

A brand new research shows that these drugs recovered 78 out of 80 patients, but something seems to be wrong with those studies…

(Article written by Lic. Julián Fernández and edited by Ed. Candela Capra Coarasa)

Chloroquine and hydroxychloroquine have been on everyone’s lips since last week. Everything started when a French study carried out by Prof. Didier Raoult showed that some patients successfully recovered from COVID-19 after being treated with said drugs [1]. However, it was not until Trump mentioned them in a press conference that they became famous.

Despite the scientific community’s skepticism around this study, the urgency for treatment and the lack of other clinical trials made chloroquine and hydroxychloroquine two of the few drugs that were selected for WHO’s “Solidarity” mega trial [2]. Moreover, the FDA approved its use in patients in case of emergency and some pharmaceuticals like Novartis donated a huge amount of these drugs to be used in patients [3].

A brand new study carried out by the same Professor has just been published [4]. In these clinical trials, the action of hydroxychloroquine is complemented by the use of azithromycin showing what, at first sight, seems to be very promising results. Nevertheless, criticism around this preprint has already arisen (as it did with the previous article), arguing (again) that the way the trial was carried out does not prove if the therapy is effective or not [5, 6].

What is going on? Why Everything Seems so Confusing?

To answer these questions, we should first understand a little bit more about Prof. Didier Raoult’s studies.

Why Azithromycin?

Azithromycin is an antibiotic that has been around for a while. As we mentioned in our previous article, one of the main strategies scientists have is drug repurposing. This consists of using old drugs, which safety profile is already known, for treating diseases different from the one they were made for. This was the case for chloroquine and hydroxychloroquine, and it also is for azithromycin. The latter was first discovered in 1980 in the former Yugoslavia and approved for medical use in 1988. It is now used for battling many bacterial infections and it is one of the historical bestsellers in the pharmaceutical industry that made it to WHO’s “List of essential drugs” [7].

But, why did they select an antibacterial for the treatment of a virus?

Well, there are some reasons that make this drug an excellent choice. First of all, its antiviral activity has already been proved in the past against Zika and Ebola viruses [8,9]. Secondly, it’s usually used for the prevention of respiratory tract infections [10]. Finally, and probably the main reason why this molecule was selected, is that it can be used for the treatment of malaria in combination with chloroquine or hydroxychloroquine [11,12,13]. It is important that previous uses of azithromycin in combination with the others have already been reported, considering that drug to drug interactions may be harmful to the patient.

Latest Studies and Reasons for Skepticism

As of today, there are two main studies carried out in patients regarding the use of hydroxychloroquine and/or azithromycin and both belong to French Prof. Didier Raoult. Each of them showed very promising results at first but, in the end, both turned out being controversial.

The first study, which was finally published on March 20, reported the first time these drugs were used for the treatment of patients infected with SARS-coV-2 [1].

In summary, a total of 26 patients received hydroxychloroquine from the beginning of the trial with another 16 used as control patients (this is particularly important, and we will come back to it later). Depending on their clinical presentation, azithromycin was administered as antibacterial (6 patients in total). In the end, from the final number of 20 patients evaluated during the whole trial, the ones treated with both hydroxychloroquine and azithromycin were the ones who recovered faster, suggesting that further studies on this therapy needed to be done.

However, this study had some significant counterpoints. The first, and more obvious one, is that the number of patients used in this trial was too small. Secondly, another remarkable issue was the inability to do follow up on six patients, which constitutes around 23% of the treated sample, which is a huge percentage. Finally, the last source of criticism lies in the fact that it was not a randomized trial [5, 6].

All in all, despite the lack of accuracy in this first trial, and considering the enormous patients’ urgency for treatment, this initial study is for sure an important contribution to science right now.

Something that for sure comes out of this last research is that the effectiveness of hydroxychloroquine in conjunction with azithromycin must be explored further. With this goal in mind, Prof. Raoult’s team carried out the second trial, which preprint was uploaded to their website last Friday.

In this case, 80 patients were treated with this drug combination, and their performance was monitored for several days. The outcome seems incredible: all patients improved, and their viral load decreased dramatically in five days. Only two out of 80 showed some inconvenience, an 86 year-old patient died and another 74-year-old patient was still in the ICU when the manuscript was published [4]. Up to this point, everything seems legit and promising, but several observations must be made about this trial.

The most important aspect that critics point out is that this trial lacks a control group [4, 5, 6]. This is particularly strange, considering that there was a control group in the first trial.

In any scientific experiment, a control group is a vital part of the process. Without any non-treated patients in the trial, how can anyone measure if the drug is being effective or not? It just can’t be done.

It is impossible to know if the patients would have recovered just as well if the drugs hadn’t been administered.

Two other important aspects are also being criticized and both focus on the patients themselves. First of all, the manuscript does not publish any individual information about these 80 patients. This way it is impossible to do individual follow ups and, for example, explain how some of them recovered in just one day (maybe they were already about to be discharged). And finally, an aspect that is complementary to the previous ones, is that most patients were experiencing mild cases of the disease: some were even asymptomatic [4, 5, 6].

What if the patients discharged in the first days were asymptomatic or just about to get better? Was it the treatment that helped them or would they have been equally discharged otherwise?

Questions like the one above can’t be answered right now.

Final Thoughts

In conclusion, skepticism around both studies is well founded. Moreover, some experts argue that this last trial is completely useless due to the absence of a control group, and they might be right.

On the other hand, considering that most likely the death of the 86 year-old patient was not because of this treatment (again, hard to tell without a control group), it is feasible that this drug combination is harmless to humans under COVID-19. What is morre, if we also take into account that there are zero available treatments and very few experimental options, it is understandable that this conjuncted therapy is taken into account when it comes to a patient that has no other option.

There is a good chance that over the next few days this Hydroxychloroquine/Azithromycin treatment will be all over the news, so it’s important to proceed with caution.

For the many reasons explained above, we should wait for further studies to be made before we start thinking of this treatment as our salvation.

References

[1] Gautret, Philippe, et al. “Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial.” International Journal of Antimicrobial Agents, 2020, p. 105949.
[2] WHO launches global megatrial of the four most promising coronavirus treatments Science
[3] Novartis donates malaria drug for COVID-19 clinical trials PMLive
[4] https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf
[5] More on Chloroquine/Azithromycin. And On Dr. Raoult. In the Pipeline
[6] Hydroxychloroquine and azithromycin versus COVID-19: Grift, conspiracy theories, and another bad study by Didier Raoult Science-Based Medicine
[7] Azithromycin
[8] E Bosseboeuf, M Aubry, T Nhan, JJ de Pina, JM Rolain, D Raoult, et al. Azithromycin inhibits the replication of Zika virus J Antivirals Antiretrovirals, 10 (1) (2018), pp. 6–11,
[9] PB Madrid, RG Panchal, Warren, AC Shurtleff, AN Endsley, CE Green, A Kolokoltsov, et al. Evaluation of Ebola Virus Inhibitors for Drug Repurposing ACS Infect Dis, 1 (7) (2015 Jul 10), pp. 317–326
[10] LB Bacharier, TW Guilbert, DT Mauger, S Boehmer, A Beigelman, AM Fitzpatrick, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: A randomized clinical trial JAMA, 314 (19) (2015 Nov 17), pp. 2034–204
[11] Dunne MW, Singh N, Shukla M et al. A multicenter study of azithromycin, alone and in combination with chloroquine, for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J Infect Dis. 2005; 191:1582–8. http://www.ncbi.nlm.nih.gov/pubmed/15838784?dopt=AbstractPlus
[12] Miller RS, Wongsrichanalai C, Buathong N et al. Effective treatment of uncomplicated Plasmodium falciparum malaria with azithromycin-quinine combinations: a randomized, dose-ranging study. Am J Trop Med Hyg. 2006; 74:401–6. http://www.ncbi.nlm.nih.gov/pubmed/16525097?dopt=AbstractPlus
[13] Noedl H, Krudsood S, Chalermratana K et al. Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomized, phase 2 clinical trial in Thailand. Clin Infect Dis. 2006; 43:1264–71. http://www.ncbi.nlm.nih.gov/pubmed/17051490?dopt=AbstractPlus