4. Hydroxychloroquine

Today we’re focusing on a hot topic – the use of chloroquine and hydroxychloroquine for treatment of COVID-19. This drug had a lot of buzz early on, but recent data has been lukewarm at best.

 

Background: why chloroquine?

Chloroquine and hydroxychloroquine are old medications generally used for the treatment of malaria, amebiasis, and certain inflammatory conditions like rheumatoid arthritis. These medications have anti-viral activity in vitro, but there is no demonstrated clinical efficacy in treatment of viral illness There are several proposed mechanisms including immunomodulatory/immunosuppressive effects – which, it should be noted, may potentially be harmful in the setting of viral disease Chloroquine isn’t available in Canada. Hydroxycholorquine is, but due to the recent media frenzy, the supply is unstable and there are very real concerns that patients who need these drugs for legitimate indications may have difficulty accessing them

 

 

In-vitro and animal data

There is some in-vitro data of chloroquine and hydroxychloroquine activity against COVID-19; and some data informing potentially effective doses1,2 Animal data is not supportive – one study of chloroquine in mice with SARS was negative3

 

Human data

There was a lot of buzz about this drug early on and hype from some very small/low-quality studies Gautret (2020)4: this was a much-discussed very small French trial of 26 patients hospitalized with COVID-19 (though note that some of them were actually asymptomatic!) They all received hydroxycholorquine; 6 also received azithromycin Non-randomized; control group was patients who refused treatment Their primary endpoint was negative viral PCR on day 6 This was lauded as a positive study as all patients who received both drugs had viral clearance at 6 days; vs 57% of the patients who had hydroxychloroquine only; and 12% of controls HOWEVER – a lot of caveats here: high loss to follow up, high potential for bias, non-clinical endpoint Gao (2020)5: this was a publication stating that “chloroquine use in 100 patient is superior to the control treatment for inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting virus negative conversion, and shortening the disease course” – but no patient data was published Chen (2020)6: randomized trial of hydroxychloroquine use in patients with mild illness 62 patients in a Wuhan hospital with mild illness only Patient were randomized to 200mg BID of hydroxychloroquine vs control Their primary outcome as a time to clinical improvement They reported improved numbers in the treatment group BUT v small numbers, no mention of statistical significance, arguably relevant clinical endpoint Higher-quality data has now emerged showing no benefit to HCQ, and potential harm Magagnoli (2020)7 Retrospective cohort analysis of patients admitted to VA hospitals in the US with exposure to hydroxychloroquine, hydroxychloroquine and azithromycin, or neither drug Adjusted risk of death was higher in the HCQ group (HR 2.61) Unadjusted mortality was higher in both HCQ and HCQ + AZA groups compared to no Tx (27.8% vs 22.1% vs 11.4% respectively) Borba (2020)8 Randomized clinical trial of low vs high-dose hydroxychloroquine for severe COVID 450mg BID on day 1, then daily x 4d vs 600mg BID x 10d Interim analysis recommended early termination of the trial after enrollment of 81 of a pre-planned 440 patients due to increased mortality in the high-dose group (39% vs 15%) More QTc prolongation in high-dose group Tang (2020)9 Open-label RCT for hydroxychloroquine in mild-to-moderate COVID 151 patients Intervention: 1200mg PO daily x 3d load, then 800mg PO daily for 2-3 weeks Primary outcome of viral clearance by 28 days, defined by 2 consecutive negative PCR tests Outcome: no difference (85% vs 81%); increase in adverse events in HCQ group (30% vs 7%)

 

Side effects

Have not been investigated in the setting of COVID-19 From experience with malaria and rheumatologic illnesses, hydroxychloroquine is generally well-tolerated Dose of 400mg/d max (generally) Common side effect: GI upset Less common but more potentially worrisome: hypoglycemia, skin reactions, QTc prolongation (especially in combination with other QT-prolonging agents like azithromycin!), hepatotoxicity, bone marrow suppression, and retinal toxicity (related to long-term cumulative use)

 

Bottom line

While it’s tempting to jump at any and all possible therapies right now, we need to first do no harm Despite initial promising pre-clinical data and anecdotal reports, more recent evidence on hydroxychloroquine fails to demonstrate a clinical benefit; and suggests the potential for harm, especially at high doses

 

 

Sources

Wang, M., Cao, R., Zhang, L. et al.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res30, 269–271 (2020). doi: 10.1038/s41422-020-0282-0

 

Yao X, Ye F, Zhang M et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clinical Infectious Diseases, ciaa237, doi: 10.1093/cid/ciaa237

 

Barnard D, Day C, Bailey K et al. Evaluation of immunomodulators, interferons and known in vitro SARS-CoV inhibitors for inhibition of SARS-CoV replication in BALB/c mice. Antiviral Chemistry & Chemotherapy, 2006, 17:275–284. doi: 10.1177/095632020601700505

 

Gautret P, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrobial Agents, 2020. doi: 10.1016/j.ijantimicag.2020.105949   Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioScience Trends, 2020. doi:10.5582/bst.2020.01047

 

Chen J, Liu L, Liu D et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci), 2020;49(1). doi:10.3785/j.issn.1008-9292.2020.03.03

 

Magagnoli J, Narendran S, Pereira P et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. MedRxiv pre-print, 2020. doi:10.1101/2020.04.16.20065920

 

Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open.2020;3(4):e208857. doi:10.1001/jamanetworkopen.2020.8857

 

Tang W, Cao Z, Han M. Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized, controlled trial. MedRxiv pre-print, 2020. doi: 10.1101/2020.04.10.20060558