The FLARE Four
- Initial enthusiasm for chloroquine and hydroxychloroquine for treatment of SARS-CoV-2 infection spurred a number of clinical trials, some with newly published data
- Though the majority of available clinical data have not been peer reviewed, no studies demonstrate significant differences in relevant clinical outcomes
- Furthermore, enthusiasm for these medications has waned amidst worrisome safety signals in patients receiving hydroxychloroquine and azithromycin
- We eagerly await the peer-reviewed published data from these hydroxychloroquine trials (and from the publicized, but not yet released, remdesivir NIAID trial), to further refine the armamentarium for COVID-19
Many people are still saying..."[Hydroxychloroquine] is a very strong, powerful medicine...We have some very good results and some very good tests...In France, they had a very good test."
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In the month since we first commented on the use of chloroquine (CQ) and hydroxychloroquine (HCQ) (March 22 FLARE), there has been a flurry of scientific activity and media interest in repurposing these drugs as therapy for treating patients with COVID-19. This was particularly spurred by a study claiming improved SARS-CoV-2 viral clearance by HCQ (Gautret et al. 2020), a publication which is now undergoing additional independent peer review. There has also been increasing recognition of potentially dangerous side effects associated with HCQ. 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 (Center for Drug Evaluation and Research 2020; “Antiviral Therapy | Coronavirus Disease COVID-19” n.d.).
What Is the Scientific Rationale Underpinning the Recommendation Against Combining Hydroxychloroquine and Azithromycin for the Treatment of COVID-19?
The NIH has recommended 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 risk of potentially life-threatening ventricular arrhythmias. Concerns that co-administration of these drugs might compound risk were 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 (Ramireddy et al. 2020). A similar analysis of 84 patients at NYU Langone Medical Center treated with HCQ+AZ revealed that 11% developed QTc prolongation to a dangerous level greater than 500 ms (Chorin et al. 2020). Concerningly, neither study identified baseline QTc as a reliable predictor of severe drug-induced QTc prolongation, suggesting it may be challenging to identify those patients at highest risk prospectively. 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 (Lane et al. 2020). Together, the available observational data raise serious safety concerns that would require very strong evidence of efficacy to justify.
Inflammation and HCQ = Torsades?
Cardiac toxicities of hydroxychloroquine have been recognized from use in other indications (rheumatology, anti-malarial, etc). Hydroxychloroquine can prolong the QTc interval leading to a form of polymorphic ventricular tachycardia known as torsade de pointes (TdP). TdP is characterized by a sinusoidal appearance with periodic “twisting” of the peaks of the QRS complex around the electrocardiogram isoelectric line, with rate about 150-250 bpm. TdP is due to inhibition of the inward rectifying potassium channel (IKr) (Roden 2008); the pore forming subunit of this channel is encoded by the human ether-a-go-go-related gene (hERG). hERG/IKr plays an important role in the repolarization of cardiac myocytes and so affects the duration of the ventricular action potential. The ventricular action potential duration is reflected by the QT interval on an electrocardiogram (ECG).
Reduction of hERG current prolongs the action potential and causes a prolonged QT (Lamothe et al. 2016). The mechanism of “torsadogenesis” is related to inward cation (e.g. calcium) fluxes that occur during the prolonged ventricular repolarization interval. These are called “early after depolarizations”, and may relate to variations in the QTc interval, such as due to ectopic beats, and may be more frequent with slower ambient heart rate. Such depolarizations create an action potential that may propagate variably in some myocytes, thereby causing a reentrant excitation of myocytes, and driving tachyarrhythmia. While TdP can occur in self-resolving salvos, multiple salvos can recur in repetitive fashion and degenerate to ventricular fibrillation.
Despite the known cardiac risks associated with its use, hydroxychloroquine has generally been well-tolerated when used for non-COVID indications (Ruiz-Irastorza et al. 2010). There may be a higher risk of complications in the setting of concomitant QTc-prolonging medications (such as azithromycin), renal injury, and metabolic aberrations (hypokalemia or hypomagnesemia). These can be seen in COVID-19 (Saleh Moussa et al., n.d.). Certain inflammatory cytokines (TNF-alpha, IL-1, IL-6) can also contribute to QTc prolongation by impacting ion channel gene expression, or IL-6 mediated suppression of IKr (El-Sherif, Turitto, and Boutjdir 2019). The relevance of such observations to COVID-19 related pathophysiology is not yet known.
Is There Evidence of Efficacy?
In addition to the basic science (laboratory) evidence we discussed last month (March 22 FLARE), there have now been several clinical reports regarding safety and efficacy of these medications in patients. The majority of data have come by way of “pre-prints” which facilitate rapid dissemination of results but have not been through the process of peer review.
Clinicaltrials.gov lists over 100 active studies that involve HCQ treatment of COVID-19 patients. The available data from pre-prints do not support a major therapeutic effect for HCQ in COVID-19, with the caveats that (1) definitive data from large, well-controlled randomized trials are still lacking and (2) that it is difficult to rule out the possibility that specific patient populations (yet to be identified) might benefit. As of late April, results from five randomized trials of CQ or HCQ have been reported. The three available Chinese RCTs report either no benefit to therapy or mild possible benefits. J. Chen and colleagues randomized 30 patients in Shanghai to 400mg HCQ daily or usual care and found no change in rate of nasal viral clearance; only one patient worsened to severe disease and was in the HCQ-treated group (Jun et al. 2020). Z. Chen and colleagues randomized 62 mild COVID-19 patients to 400mg HCQ daily or usual care, reporting 1-day reduction in fever and cough during the study period; 4 patients, all in the control group, worsened to severe disease (Chen et al. 2020). 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 (Tang et al. 2020). Another Brazilian study evaluated high-dose versus low-dose CQ in 81 patients, and fifth trial compared CQ to lopinavir/ritonavir (a repurposed HIV protease inhibitor) in 22 Chinese patients (Huang et al. 2020; Borba et al. 2020).
In addition to these five randomized trials, three non-randomized studies (one from the United States and two from France) have analyzed outcomes and adverse effects in a total of 585 COVID-19 patients, of which 314 received HCQ (Magagnoli et al. 2020; Mahevas et al., n.d.; Gautret et al. 2020). Of the retrospective trials of HCQ, the largest analyzed outcomes in American COVID-19 patients treated with HCQ (n=97), HCQ+AZ (n=113), or neither (n=158) (Magagnoli et al. 2020). 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 mortality. A French study of 84 HCQ-treated and 97 non-treated hospitalized COVID-19 patients failed to identify differences in mortality or ICU transfer but found 10% of HCQ-treated patients had ECG changes requiring drug discontinuation (Hulme et al. 2020). One published case series described 17 COVID-19 patients with lupus who had already been receiving HCQ therapy and found their clinical trajectories and outcomes to be very similar to those reported for COVID-19 generally (Mathian et al. 2020). While reports without control groups should not be used to guide clinical decision making, this observation certainly argues against the notion that HCQ alone is sufficient to block infection or impact clinically significant illness due to SARS-CoV-2.
Taken together, preliminary reports suggest 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 are forthcoming, including from the PETAL network ORCHID trial, which is currently enrolling. Until such time as those data become available, these drugs are best utilized in investigational settings with careful safety monitoring.
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