COVID-19 & Hydroxychloroquine: Does It Work…

Dermatologists for years have used Plaquenil (Hydroxychloroquine) to treat many chronic, often inflammatory, conditions, such as erosive lichen planus (LP), discoid lupus erythematosus (DLE), systemic lupus erythematosus (SLE), dermatomyositis, frontal fibrosing alopecia, and morphea.  Chloroquine is a sister drug used to treat malaria, they are very similar medications. Chloroquine was synthesized in Germany by Bayer in 1934 and was marketed as an effective substitute for natural quinine some 70 years ago.  Hydroxychloroquine was subsequently developed as an alternative to treat malaria, it had a faster absorption time and less overall toxicity compared to Chloroquine.  For the most part these medications are very well tolerated with few serious adverse events (SAE).  I have had patients on Plaquenil for many months to years.  The most significant long term complication is the potential for retinopathy.  I have my patients examined by an ophthalmologist once a year.  Other potential serious side effects are mostly cardiac (arrhythmia, prolonged QT intervals and torsades de pointes) but this occurs usually with an overdose.  Other reported SAEs include blood and lymphatic disorders, and hepatobiliary disorders, although extremely rare and usually in patients on long term treatment.  In treating the masses for malaria and malaria prophylaxis the most immediate concern is patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency that can develop an acute hemolytic anemia.  In all my years of prescribing this drug I have not had any patients with G-6-PD.  To read more about uses and SAEs click HERE, HERE, HERE, and HERE.

SAFETY PROFILE FOR SHORT TERM USE:  Naturally one would expect that use of the drug for short term treatment, such as 1-2 weeks, would increase the safety profile of the drug, and this is what I believe.  Treating patients for COVID-19 should only require pulsed therapy, allowing the patient’s own immune system to catch up to the infection, eventually clearing the virus.

STUDIES OF HYDROXYCHLOROQUINE (PLAQUENIL) AND CHLOROQUINE IN TREATING CORONAVIRUS INFECTIONS:  COVID-19 is not unique.  It is a coronavirus, just like H1N1 (Swine Flu), SARS, and Spanish Flu, and any studies performed on these various flu viruses should be able to be applied to this newest version of the virus.  Let’s review the literature that is available…

  1. Romanelli, et al, reported clinical responses in HIV patients being treated with Chloroquine and Hydroxychloroquine in 2004 (click HERE) as measured by decreased viral load.  This demonstrated that these drugs may have significant antiviral value.  It has also been shown to be useful in treating Zika virus (click HERE), and influenza (click HERE).
  2. Keyaerts, et al, reported in 2004 that Chloroquine can be highly effective against coronavirus (HCoV-OC43) in infection of newborn mice (click HERE).  Fascinating study.  The authors observed the death rate in newborn mice where the mother was infected with the virus.  Chloroquine given to pregnant females crossed transplacentally and in breast milk, resulting in 98.6% surviving at doses of 15 mg/kg, 88% survival at 5 mg/kg and 13% at 1 mg/kg.
  3. Keyaerts, et al, followed their mice study (2004) with an examination of in vitro responses of SARS virus to Chloroquine in tissue culture (click HERE).  The authors demonstrated IC50 of Chloroquine for antiviral activity was significantly lower than its cytostatic activity at concentrations that were equivalent to plasma levels of patients treated for malaria.
  4. Vincent, et al, studied the use of Chloroquine as an inhibitor of SARS coronavirus infection and spread of infection in tissue culture in 2005.  The authors demonstrated inhibitory effects when the cells were treated with the drug either before or after exposure to the virus suggesting both prophylactic and therapeutic advantages.  Chloroquine blocks viral infection by increasing endosomal pH required for virus/cell fusion, as well as interfering with glycosylation of cellular receptors of SARS.  To read this article click HERE.

Studies on COVID-19:

  1. Wang, et al, reported on a number of potential therapeutic agents–Ribavirin, Penciclovir, Favipiravir, Nafamostat, Nitazoxanide, Remdesivir and Chloroquine–against COVID-19 viral reproduction in tissue culture.  Many of these drugs were utilized in treating patients with SARS.  The results of this study showed that Remdesivir and Chloroquine were highly effective in controlling COVID-19 in vitro (click HERE).
  2. Gao, et al, reported a letter noting that Chloroquine phosphate was being added to the drug therapies for COVID-19 issued by the National Health Commission of the People’s Republic of China based on Chinese Clinical Trial Registry (click HERE, and HERE).  In 10 hospitals (over 100 patients) with COVID-19 associated pneumonia treated with Chloroquine or Hydroxychloroquine were superior to controls in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus-negative conversion and shortening the disease course.
  3. Gautret, et al, (France) performed an open-label non-randomized clinical trial using Hydroxychloroquine to treat 22 patients with active disease.  Some patients were also treated with Azithromycin in combination with Hydroxychloroquine.  The authors followed many parameters including clinical improvement and measured viral load.  The authors were able to demonstrate decreased viral load, clearing of viral nasopharyngeal carriage in just 3-6 days (click HERE).  These results are important because the mean duration of viral shedding in China was 20 days (click HERE).  It was also determined that Hydroxychloroquine (Plaquenil) was more potent against the virus than Chloroquine and has a safer dose-dependent toxicity profile than Chloroquine.  The authors also note that Azithromycin has been shown to be active in vitro against Zika and Ebola viruses.  Patients with combined Hydroxychloroquine and Azithromycin therapy did very well and the combination therapy is highly recommended…patients treated with combination therapy cleared nasopharyneal swabs much faster.
  4. Yao, et al, reported on in vitro tissue culture results that demonstrated more potent antiviral activity for Hydroxychloroquine when compared to Chloroquine (click HERE).  Based on these results, a loading dose of 400 mg twice daily of Hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg twice daily for 4 days is recommended for treating COVID-19.
  5. Fantini, et al, discovered a new mechanism for the action of Chloroquine and hydroxychloroquine against COVID-19 (click HERE).  The first step in viral replication is the attachment to the surface of respiratory cells mediated by the spike (S) viral protein.  The S proetin uses the ACE-2 receptor for entry, but also sialic acids linked to host cell surface gangliosides.  The authors demonstrated that Chloroquine, and the more active derivative Hydroxychloroquine, binds sialic acids and gangliosides with high affinity…preventing the viral spike from binding with gangliosides on respiratory cell surfaces.
  6. Devaux, et al, published a nice review on the antiviral effects of Chloroquine and Hydroxychloroquine against COVID-19 (click HERE).  Chloroquine studies in vitro have shown antiviral activity against all RNA viruses (rabies, poliovirus, HIV, hepatitis A, hepatitis C, influenza A & B, Chikungunya, Dengue, Zika, Lassa, Hendra & Nipay, Crimean-Congo hemorrhagic fever, and Ebola).  The drugs have been shown to interfere with post-translational modification of viral protein.  Effects on pH modulation can impair the proper maturation of viral proteins and the recognition of viral antigen by dendritic cells, which occurs through a Toll-like receptor-dependent pathway that requires endosomal acidification.  Chloroquine has been shown to act on the immune system through cell signalling and regulation of pro-inflammatory cytokines…and this is why we use it in dermatology, having therapeutic benefits in many inflammatory diseases such as rheumatoid arthritis, lupus erythematosus, and sarcoidosis.
  7. On March 28, 2020 the FDA issued an Emergency Use Authorization (EAU) to allow Hydroxychloroquinne sulfate and Chloroquine phosphate for use in treating COVID-19 patients.

IS THIS PROOF ENOUGH…

Dermatologist have a long history of treating patients with drugs off label.  That’s because many of the diseases that we come across are extremely rare, and it is difficult to collect enough of a patient population to randomize into double-blind, placebo-controlled studies.  We often have to rely on case reports, small series of open-labeled trials, retrospective studies or multivariate regression of pooled studies.

It is always best to perform double-bind, placebo-controlled studies, and numerous ones are currently being planned and implemented for the treatment of this disease.  These studies are complex and take many months to years to complete the various phase 1, 2, and 3 clinical trials to finally determine that the drug is safe and effective.  Needless to say, we don’t have any of these for COVID-19.  Reviewing the studies currently available I believe, and the FDA believes, that there is enough data to support the use of Hydroxycholorquine and Chloroquine for the treatment of COVID-19 patients.  Combination therapy with Hydroxychloroquine and Azithromycin is highly recommended.