Is There Evidence Hydroxychloroquine Works on COVID-19?

Check out this answer from Consensus:

The current body of research suggests that hydroxychloroquine is not effective in reducing mortality or preventing severe outcomes in COVID-19 patients. Its use as a prophylactic agent also shows no significant benefit. Additionally, HCQ is associated with a higher risk of adverse events. Therefore, the evidence does not support the use of hydroxychloroquine for treating or preventing COVID-19.

Hydroxychloroquine (HCQ) has been proposed as a potential treatment and prophylactic agent for COVID-19 due to its antiviral properties observed in vitro. However, its efficacy and safety in clinical settings have been subjects of extensive research and debate.

Key Insights

• Efficacy in Reducing Viral Load:
  • Some studies suggest that HCQ, especially when combined with azithromycin, can reduce viral load in COVID-19 patients1 10. However, these findings are based on small sample sizes and non-randomized trials, which limits their reliability.
• Mortality and Disease Progression:
  • Large-scale randomized controlled trials (RCTs) indicate that HCQ does not significantly reduce mortality or prevent progression to severe disease in hospitalized COVID-19 patients2 6 8. In fact, HCQ combined with azithromycin may increase mortality8.
• Prophylactic Use:
  • Studies on the prophylactic use of HCQ show no significant difference in preventing COVID-19 infection or symptomatic disease compared to placebo or standard care3 7. These trials also report a higher incidence of adverse events in the HCQ groups.
• Adverse Events:
  • HCQ is associated with a higher risk of adverse events, including QT interval prolongation, but does not significantly increase the risk of serious adverse events2 3 7 9.
• Conflicting and Insufficient Evidence:
  • The overall evidence on the benefits and harms of HCQ for treating or preventing COVID-19 is weak and conflicting, with many studies showing no significant clinical benefit5 9.

Is there evidence hydroxychloroquine works on COVID-19?

Euan Wallace has answered Unlikely

An expert from Monash University in Medicine, Obstetrics, Gynaecology

The short story is that there is NOT good evidence that hydroyxchloroquine (HCQ) is an effective treatment for COVID-19 and it may cause harm. Certainly HCQ is nowhere near ready for primetime.

HCQ has been assessed in 2 ways so far:

1. either by its ability to more rapidly clear COVID-19 virus from the body: one trial showed it did, and two showed it didn’t.
2. by its ability to make patient recover faster – one trial has shown it might.

All trials have been very small and far too small to make recommendations from. But there’s more…

HCQ has advrse effects, particualrly on the heart. It can lead to heart rhythm defects that may be fatal. Also, when combined with metformin – a drug taken for type 2 diabetes – it appears to have a VERY high risk of death.

So, “danger Will Robinson. Danger Will Robinson”. 

Next step, more careful clinical trials. 

Certainly HCQ is nowhere near ready for primetime.

The long story:

In March, asmall trial of HCQ was “reported” from Zhejiang in the Journal of Zhejiang University (15 patients on HCQ and 15 untreated) with viral RNA endpoints. No differences were reported. That is, HCQ “didn’t work”. However, there were a number of problems with the trial. So let’s not kill HCQ yet.

A week ago (or so), another small, blinded, randomised trial of HCQ was posted on a preprint server PubPeer (Chen Zhaowei et al), showing that, compared to placebo, 5 days treatment with HCQ shortened the time to clinical recovery and reduced likelihood of pneumonia. 62 patients in total (31 HC, 31 placebo). This was an important trial because it was the first to show any benefit of HCQ in treating COVID-19. So, HCQ works!? Too small a study to be certain. But worth doing more research. Not yet possible to say “HCQ cures COVID-19” and HCQ can cause harm, particularly in patients with heart conditions.

A study from Marseilles, published in International Journal of Antimicrobial Agents,  assessed ability of HCQ ± azithromycin to clear COVID-19 virus. 20 patients were treated and they all showed more rapid clearance, suggesting effectiveness. 

Also last week (March 30), a study published online in Medecine et Maladies Infectieuses, a trial of HCQ and azithromycin (an antibiotic) from Paris also assessed ability of HCQ and AZA to clear viral RNA – clear the disease – in 11 patients. One died and viral RNA remained present in the other 10. HCQ (+AZA) did not work.

Is there evidence hydroxychloroquine works on COVID-19?

Rebecca Burton has answered Uncertain

An expert from Oxford University in Pharmacology, Physiology, Cardiovascular Disease

As of 9th April 2020, a search on the EU Clinical Trials webpage for COVID-19 and hydroxychloroquine (HCQ) returns 21 registries [https://www.clinicaltrialsregister.eu]; there are at least 8 Chinese clinical trial registries for using HCQ to treat COVID-19 [http://www.chictr.org.cn]. Apart from these mentioned trials, there are many more such trials ongoing in various parts of the world too. The evidence for HCQ efficacy and utility in the treatment of the disease will materialise as more basic science and clinical data emerge over time. However, at this moment, clear experimental evidence is still lacking around the question of human safety and efficacy of HCQ in treating the virus SARS-CoV-2 that causes COVID-19.

Studies have shown some benefits and risks. Wang et al. 2020[1] published their lab findings, where they reported that remdesivir and chloroquine (CQ) are effective in the control of 2019-nCoV infection in vitro in Vero E6 cells (African green monkey kidney cells). Gautret et al. 2020[2] published their recent open label, non-randomised trials on HCQ and azithromycin (AZ) as a treatment of COVID-19. Whilst the outcomes reported in this paper, may appear to indicate a favourable effect on clinical outcomes (i.e. HCQ treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by AZ), the major limitations must be borne in mind when interpreting the results from this very small cohort of patients [26 patients received HCQ (of which 6 HCQ patients were lost in follow up) and 16 were control patients]. On the 3rd of April (2020), Chorin et al. 2020, deposited a paper on MedRxiv (https://doi.org/10.1101/2020.04.02.20047050), based on a retrospective study performed at NYU Langone medical center, where they report a change in the QT interval in 84 adult patients with SARS-CoV-2 infection treated with HCQ/AZ combination. Here they found that the patients treated with HCQ/AZ QTc prolonged significantly; 11% of patients, QTc prolonged to >500 ms, a known marker for high risk of malignant arrhythmia and sudden cardiac death.

HCQ has been around since the 1950’s and appears to work via multiple mechanisms and hence has shown utility in a number of disease conditions. HCQ has been used in the treatment of rheumatoid arthritis (RA) and Systemic Lupus Erythematosus (SLE), with a good safety profile including the prescription to pregnant women at appropriate doses. NICE recommends a dose of 200-400 mg daily for an adult, maximum dose to be based on ideal body-weight; maximum 6.5 mg/kg per day for RA and SLE. Back in 1958[3], Burrell and Martinez reported that CQ and HCQ proved useful in the treatment of cardiac arrhythmias. Extensive cardiac basic science studies by Capel et al in 2015[4] have shown that HCQ also inhibits the pacemaking current ‘If’ and offers the potential of being used as a bradycardiac agent. They also noted additional effects on the L-type calcium channels and delayed rectifier potassium channels in isolated guinea pig sinoatrial node cells, indicating the multichannel blocking action of HCQ in cardiac cells. Sharma et al. 2016[5] published data showing that HCQ use was associated with a 72% decrease in the risk of incident cardiovascular disease in RA patients. Whilst these effects may be beneficial in some conditions, it must be borne in mind that higher doses may become a safety risk in different patient cohorts especially severely ill patients.

Looking at this question with all the above research in mind, is HCQ useful in the treatment of COVID-19? Data to support this is limited and inconclusive[6]. The Wang paper[1] discusses CQ and remdesivir. CQ is more toxic than HCQ with known toxicity effects. Back in 2004[7] and 2005[8], CQ was shown to have strong antiviral effects on SARS-CoV infection of primate cells. But we must bear in mind these tests were done in cell cultures and the IC50 of CQ for inhibition of SARS-CoV in vitro approximates the plasma concentrations of CQ reached during treatment of acute malaria. So are we using CQ/HCQ doses to treat COVID-19 that are too high and therefore affecting the safety of the drug? Upcoming trials such as The PATCH Trial (Prevention And Treatment of COVID-19 With Hydroxychloroquine), quote dose ranges between 400 mg (twice daily) to 600 mg (twice daily). The cardiotoxicity effects that are now being reported by various studies will be linked to this question. Additionally, patient risk factors can also predispose to cardiotoxicity in the clinical setting, some of which may be more common in COVID19, e.g. electrolyte imbalances, renal failure, drug interactions. What about the effects of COVID-19 on the heart? COVID-19 seems to affect the heart (e.g. myocarditis), which may additionally increase the risk of cardiotoxicity, more detailed research is required to confirm the effect of COVID-19 on the heart.

Evidence supporting the use of antimalarial medications for COVID-19 is equivocal. Recently, CQ has been shown to be effective in COVID-19 in vitro tests demonstrating antiviral activity, but it doesn’t necessarily mean that CQ or HCQ should behave in the same way in large animal models (eg. See the Chikungunya virus caveat, CQ worked in vitro but failed in primate models of the disease). Extensive basic science research in animal models will be able to provide better insights into the utility of HCQ in COVID-19, this data will then guide clinical translation safely.

Key References:

1. Wang, M., et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res, 2020. 30(3): p. 269-271.
2. Gautret, P., et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents, 2020: p. 105949.
3. Burrell, Z.L., Jr. and A.C. Martinez, Chloroquine and hydroxychloroquine in the treatment of cardiac arrhythmias. N Engl J Med, 1958. 258(16): p. 798-800.
4. Capel, R.A., et al., Hydroxychloroquine reduces heart rate by modulating the hyperpolarizationactivated current If: Novel electrophysiological insights and therapeutic potential. Heart Rhythm, 2015. 12(10): p. 2186-94.
5. Sharma, T.S., et al., Hydroxychloroquine Use Is Associated With Decreased Incident Cardiovascular Events in Rheumatoid Arthritis Patients. J Am Heart Assoc, 2016. 5(1).
6. Yazdany, J. and A.H.J. Kim, Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic: What Every Clinician Should Know. Ann Intern Med, 2020.
7. Keyaerts, E., et al., In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun, 2004. 323(1): p. 264-8.
8. Vincent, M.J., et al., Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J, 2005. 2: p. 69.