A controversial study led by Didier Raoult, MD, PhD, on the combination of hydroxychloroquine and azithromycin in patients with COVID-19 was published March 20. The latest results from the same Marseille team, which involve 80 patients, were reported on March 27.
The investigators report a significant reduction in the viral load (83% patients had negative results on quantitative polymerase chain reaction testing at day 7, and 93% had negative results on day 8). There was a “clinical improvement compared to the natural progression.” One death occurred, and three patients were transferred to intensive care units.
If the data seem encouraging, the lack of a control arm in the study leaves clinicians perplexed, however.
Benjamin Davido, MD, an infectious disease specialist at Raymond-Poincaré Hospital in Garches, Paris, spoke in an interview about the implications of these new results.
What do you think about the new results presented by Prof. Raoult’s team? Do they confirm the effectiveness of hydroxychloroquine?
These results are complementary [to the original results] but don’t offer any new information or new statistical evidence. They are absolutely superimposable and say overall that, between 5 and 7 days [of treatment], very few patients shed the virus. But that is not the question that everyone is asking.
Even if we don’t necessarily have to conduct a randomized study, we should at least compare the treatment, either against another therapy – which could be hydroxychloroquine monotherapy, or just standard of care. It needed an authentic control arm.
To recruit 80 patients so quickly, the researchers probably took people with essentially ambulatory forms of the disease (there was a call for screening in the south of France) – therefore, by definition, less severe cases.
But to describe such a population of patients as going home and saying, “There were very few hospitalizations and it is going well,” does not in any way prove that the treatment reduces hospitalizations.
The argument for not having a control arm in this study was that it would be unethical. What do you think?
I agree with this argument when it comes to patients presenting with risk factors or who are starting to develop pneumonia.
But I don’t think this is the case at the beginning of the illness. Of course, you don’t want to wait to have severe disease or for the patient to be in intensive care to start treatment. In these cases, it is indeed very difficult to find a control arm.
In the ongoing Discovery trial, which involves more than 3,000 patients in Europe, including 800 in France, the patients have severe disease, and there are five treatment arms. Moreover, hydroxychloroquine is given without azithromycin. What do you think of this?
I think it’s a mistake. It will not answer the question of the effectiveness of hydroxychloroquine in COVID-19, especially as they’re not studying azithromycin in a situation where the compound seems necessary for the effectiveness of the treatment.
In addition, Discovery reinforces the notion of studying Kaletra [lopinavir/ritonavir, AbbVie] again, while Chinese researchers have shown that it does not work, the argument being that Kaletra was given too late (N Engl J Med. 2020 Mar 18. doi: 10.1056/NEJMoa2001282). Therefore, if we make the same mistakes from a methodological point of view, we will end up with negative results.