Abstract: 1 Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an 2 Open-Label Non-Randomized Clinical Trial: Response to David Spencer (Elsevier) 3 Didier Raoult1,2, Matthieu Million1,2, Philippe Gautret1,3, Jean-Christophe Lagier1,2, Philippe 4 Colson1,2, Philippe Parola1,3, and Jean-Marc Rolain1,2 5 Affiliations : 6 1 IHU-Méditerranée Infection, Marseille, France 7 2 Aix Marseille University, IRD, AP-HM, MEPHI, Marseille, France 8 3 Aix Marseille University, IRD, AP-HM, SSA, VITROME, Marseille, France 9 Corresponding author: Didier Raoult, IHU - Méditerranée Infection, 19-21 boulevard Jean 10 Moulin, 13005 Marseille, France. Tel.: +33 413 732 401, Fax: +33 413 732 402; email: 11 didier.raoult@gmail.com 12 Key words: SARS-CoV-2; COVID-19; hydroxychloroquine; azithromycin 13 We thank the authors for the comments provided for our article (1-3), but we would like to 14 clarify key points for the story of this manuscript (4) that are critical in the context of COVID- 15 19 outbreak and for the perspective of this work. When COVID-19 starts around the world the 16 Editor-In-Chief of the Journal International Journal of Antimicrobial Agents (JM. Rolain) 17 asked colleagues (D. Raoult, PR. Hsueh, and S. Stefani) to launch a special issue in the 18 journal to create a real-time rapid debate around this emerging disease with special regards to 19 therapeutic options (5). Our preliminary paper (4) in this way was relatively trivial i.e 20 reported, in an emergency situation, a comparative analysis between a small group treated 21 with hydroxychloroquine and another small group not treated with hydroxychloroquine 22 showing a significant decrease of viral shedding after 6 days of therapy. 23 Surprisingly, despite the very small size of the group, the addition of azithromycin 24 made a difference on the endpoint we chose, which is the disappearance of the viral load in 25 the pharynx that is the only data that can be analyzed on a small group. Indeed, neither 26 mortality, nor the passage in intensive care unit, nor the duration of the treatment can be 27 evaluated on such a small group. This preliminary information was essential in our opinion 28 especially as it confirmed the preliminary in vitro and in vivo results against SARS-CoV-2 29 announced by the Chinese (6-8), also confirming previous in vitro reports on the anti-SARS- 30 CoV-1 coronavirus activity dating back to 2004 (9-12). This preliminary report paved the way 31 for work testing its reproducibility. 32 On the therapeutic level, the hydroxychloroquine + azithromycin combination was 33 found to be the most effective (4) consistent with in vitro synergistic antiviral activity 34 reported in our laboratory (13). Azithromycin had already, contrary to what one of the authors 35 says, been tested effectively on Zika (14,15), so we knew that it had an antiviral action. With 36 regard to our seminal paper on in vivo anti-SARS-CoV-2 activity of hydroxychloroquine (4), 37 we were subjected to unprecedented violence. I (DR) was asked to confess that I had a 38 relationship and a conflict of interest with Sanofi, which is laughable when you use generics 39 and you have had no relationship with the pharmaceutical industry at all at IHU (our center) 40 for 5 years. At the same time, the authors who published on remdesivir, for those we know, 41 the French, did not declare any conflict of interest in..