In This Article
- There has been a flurry of scientific activity and media interest in repurposing hydroxychloroquine and chloroquine as therapies for patients with COVID-19
- Recently, based on clinical data in the United States and elsewhere, the FDA and the NIH have each released formal statements expressing concern regarding the safety and efficacy of these agents
- In his second Q&A on the subject, Dr. Chivukula gives an update on the use of these drugs to treat COVID-19
- He concludes from the available studies that hydroxychloroquine is unlikely to be of dramatic benefit in patients infected with SARS-CoV-2 and certainly has the potential for harm, particularly when administered with azithromycin
- High-quality randomized trial data is forthcoming and, until that time, these drugs are best utilized in investigational settings with careful safety monitoring
In the month since sharing commentary from Raghu Chivukula, MD, PhD, on the use of chloroquine (CQ) and hydroxychloroquine (HCQ), there has been a flurry of scientific activity and media interest in repurposing these drugs as a therapy for treating patients with COVID-19. Recently, based on clinical data in the United States and elsewhere, the U.S. Food and Drug Administration and the National Institutes of Health have each released formal statements expressing concern regarding the safety and efficacy of these agents.
In this new Q&A, Dr. Chivukula, a physician-scientist in the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital, gives us an update on the use of these drugs to treat COVID-19.
Q: What studies have been performed to date using chloroquine and/or hydroxychloroquine to treat COVID-19?
Chivukula: In addition to the basic science (laboratory) evidence I discussed last month, there have now been several reports regarding the safety and efficacy data of these medications in patients. Before delving into the studies, it is critical to reiterate that all publications are not created equal and, to date, I would not consider any of the available clinical evidence to be of particularly high quality. Moreover, the majority of data has come by way of "pre-prints," which facilitate the rapid dissemination of results but have not been through the process of peer review.
In general, the highest quality evidence for drug treatments arises from randomized controlled trials (RCTs)—ideally blinded and placebo-controlled. As of late April 2020, results of five randomized trials of CQ or HCQ have been reported. Three of these studies (published on MedRxiv, MedRxiv, J Zheijang Univ), which enrolled a total of 242 patients in China, randomized COVID-19 patients to receive HCQ or usual care. One study in MedRxiv evaluated high-dose versus low-dose CQ in 81 Brazilian patients and another, published in the Journal of Molecular Cell Biology, compared CQ to lopinavir/ritonavir (a repurposed HIV protease inhibitor) in 22 Chinese patients. In addition to these five randomized trials, three non-randomized studies (a MedRxiv study from the United States and two from France: MedRxiv, Int J Antimicrob Agents) have analyzed outcomes and adverse effects in a total of 585 COVID-19 patients, of which 314 received HCQ. Finally, several case series (without any control groups) have described clinical courses and adverse effects in patients receiving HCQ and/or azithromycin (AZ).
Q: What is the scientific rational that backs the recommendation against combining hydroxychloroquine and azithromycin for the treatment of COVID-19?
Chivukula: The NIH recommends against combination therapy with hydroxychloroquine and azithromycin primarily due to safety concerns. As discussed last month, each of these medications is known to prolong the electrocardiogram QTc interval and thereby increase the risk of potentially life-threatening cardiac arrhythmias. Concerns that co-administration of these drugs might compound risk were evidently well-founded.
A pre-print case series of nearly 100 patients at Cedars-Sinai Hospital who received HCQ, AZ, or both revealed prolongation of QTc intervals in most patients—particularly in those receiving combination therapy. A similar analysis of 84 patients at NYU Langone Medical Center treated with HCQ+AZ found 11% of patients to develop QTc prolongation to a dangerous level (>500ms). Concerningly, neither study identified baseline QTc as a reliable predictor of severe drug-induced QTc prolongation, suggesting it may be challenging to prospectively identify those patients at highest risk. Finally, an analysis of electronic health records and administrative claims databases incorporating more than a million rheumatoid arthritis patients found that even short-term treatment with HCQ+AZ (versus HCQ plus amoxicillin) was associated with risk of angina, heart failure and cardiovascular mortality.
Together, the observational data available to date raise serious safety concerns that would require very strong evidence of efficacy to justify—as reviewed below, such evidence is lacking.
Q: Are any of the ongoing studies seeing any positive results?
Chivukula: My opinion is that the available data do not support a major therapeutic effect for HCQ in COVID-19, with the caveats that:
- Definitive data from large, well-controlled randomized trials are still lacking
- It is difficult to rule out the possibility that specific patient populations (yet to be identified) might benefit
The three available Chinese RCTs report either minimal or no benefit to patients treated with hydroxychloroquine:
- J. Chen and colleagues randomized 30 patients in Shanghai to 400mg HCQ daily or usual care and found no change in the rate of nasal viral clearance. Only one patient worsened to severe disease and was in the HCQ-treated group
- Z. Chen and colleagues randomized 62 mild COVID-19 patients to 400mg HCQ daily or usual care, reporting a 1-day reduction in fever and cough during the study period; 4 patients, all in the control group, worsened to severe disease
- Tang and colleagues randomized 150 patients to 800mg HCQ daily or standard of care and found no difference in PCR conversion rate or symptom alleviation; a higher rate of adverse events (30%) was reported in HCQ-treated patients
Of the retrospective studies of HCQ, the largest analyzed outcomes in American COVID-19 patients treated patients with HCQ (n=97), HCQ+AZ (n=113) or neither (n=158). Drug therapy was not associated with a statistically significant difference in need for mechanical ventilation, though a trend toward less mechanical ventilation was present in HCQ+AZ-treated patients; notably, HCQ-treated patients had higher rates of death.
A French study of 84 HCQ-treated and 97 non-treated hospitalized COVID-19 patients failed to identify differences in risk of death or ICU transfer, but found 10% of HCQ-treated patients had ECG changes requiring drug discontinuation. Finally, one interesting case series described 17 COVID-19 patients with lupus who had already been receiving HCQ therapy, finding their clinical trajectories and outcomes to be very similar to those reported for COVID-19 generally.
While reports without control groups should not be used to guide clinical decision-making, this observation certainly argues against the notion that HCQ alone precludes infection or illness due to SARS-CoV-2.
Taken together, my conclusion from the available studies is that hydroxychloroquine is unlikely to be of dramatic benefit in patients infected with SARS-CoV-2 and certainly has the potential for harm, particularly when administered with azithromycin as has been proposed. High-quality randomized trial data is forthcoming and, until that time, these drugs are therefore best utilized in investigational settings with careful safety monitoring.
To learn more about chloroquine, please read Dr. Chivukula's first Q&A.
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