Introduction

Chloroquine has been used for 70 years against malaria and amebiasis. Hydroxychloroquine is a similar aminoquinoline chloroquine, with a similar mechanism of action and less toxicity. Used in prophylaxis (in regions with no-reports of resistance to chloroquine) and treatment of uncomplicated malaria (caused by P. falciparum, P. malariae, P. ovale or P. vivax). Also in the management of patients with acute and chronic rheumatoid arthritis, chronic discoid lupus erythematosus and systemic lupus erythematosus, due to its anti-inflammatory properties. It is in phase II being evaluated as an immunomodulator for the treatment of HIV infection.

Hydroxychloroquine has a wide volume of distribution and a prolonged elimination half-life of about 22 days. About 20% of the dose is eliminated via the kidneys without modification. It accumulates in the lysosomes of the parasite, disturbing its growth and replication. It also accumulates in human lysosomes leading to a reduction in the antigen-triggered inflammatory response.

The in-vitro antiviral activity of chloroquine and hydroxychloroquine has been documented for several viruses, but this does not mean that they have clinical efficacy. As examples, chloroquine did not prevent influenza infection in a randomized, double-blind, placebo-controlled clinical trial and had no effect in dengue-infected patients in a randomized controlled trial in Vietnam.^1,2

This in-vitro antiviral effect has substantiated the need to implement randomized, double-blind, placebo-controlled trials to justify the use of chloroquine analogues in patients infected with zoonotic coronaviruses, as they are currently being carried out.

In the case of the SARS-CoV-1 virus, chloroquine increases endosomal pH and appears to interfere with terminal glycosylation of the cellular receptor, ACE2.³ This could negatively affect virus-receptor binding.^4,5

On the other hand, Rosenke, K et al.⁶ tested the drug in two animal models and concluded that their preclinical animal studies do not support the use of HCQ in the prophylaxis / treatment of COVID-19.

Evaluation of previous trials indicates that, to date, no acute viral infection has been successfully treated with chloroquine and congeners in humans.

On the other hand, the toxicity of chloroquine and hydroxychloroquine can be severe because higher doses would be required than for malaria. Overdose patients may present with headaches, visual disturbances, macular retinopathy, neuropsychiatric effects, seizures, cardiovascular collapse, hypokalemia, hypoglycemia, cardiac conduction disorders that may include QT prolongation, torsades de pointes, ventricular tachycardia, and ventricular fibrillation, which may further aggravated by combined use with azithromycin. This cardiotoxicity can be detrimental to occur in patients with myocardial injury due to COVID-19.

Status until: July 17, 2020

Vicent, MJ et al.³ reported observing an inhibition of the spread of SARS-CoV-1 in cell culture (an African green monkey kidney cell line).

Guilliams, EA et al.⁷ observed a 25-30% decrease in the occurrence of bacterial respiratory and gastrointestinal infections in children with malaria treated with chloroquine-azithromycin compared to chloroquine monotherapy in Blantyre, Malawi.

Yao, X et al.⁸ observed that hydroxychloroquine (EC50 = 0.72 μM) is more potent than chloroquine (CE50 = 5.47 μM) in vitro. They recommend the use of a 400 mg twice daily loading dose of orally administered hydroxychloroquine sulfate, followed by a maintenance dose of 200 mg twice daily for 4 days for SARS-CoV-2 infection.

Wang, M et al.⁹ evaluated five FDA-approved drugs and two broad-spectrum antivirals with activity against SARS-CoV-2 in vitro. One of their conclusions was that chloroquine was highly effective in controlling the 2019-nCoV infection in vitro and that due to its history it is suggested that it should be evaluated in human patients suffering from this new coronavirus disease.

Tang, W et al.¹⁰ conducted an open, multicenter, randomized trial in patients admitted to the hospital with Covid-19. The patients were recruited from 16 Treatment Centers in three provinces of China, (Hubei, Henan and Anhui). It included 150 patients, 75 were assigned to the standard care pharmacological treatment in China and 75 to the same treatment plus hydroxychloroquine, in high doses, for two or three weeks depending on the severity of the patients. The results did not show additional benefits of virus elimination by adding hydroxychloroquine to the current standard of care for patients with Covid-19 in that country. No patient died.

Mahévas, M et al.¹¹ carried out an observational study, using data collected from medical records of patients (n=181) with COVID-19 pneumonia and those who required oxygen, admitted to four French hospitals, where 92 patients received treatment with hydroxychloroquine and 89 did not receive it. The treatment had no effect on reducing intensive care admissions or mortality on day 21 after hospital admission. 10% of the patients treated with the drug had to stop it due to disorders in the electrocardiogram.

Geleris, J et al.¹² conducted an observational study where they examined the association between the use of hydroxychloroquine and the need for intubation or the occurrence of death in patients admitted for COVID-19. The study was conducted in New York City - Presbyterian Hospital (NYP) - Columbia University Irving Medical Center (CUIMC). The analysis involved a large sample of consecutive patients (n=1,446) who had been hospitalized for COVID-19. It was observed that the use of hydroxychloroquine was not-associated with a significantly higher or lower risk of intubation or death (risk ratio, 1.04; 95% CI, 0.82 to 1.32). The authors report that the study should not be taken to rule out benefit or injury from hydroxychloroquine treatment, given the observational design and 95% confidence interval, but that these results do not currently support the use of hydroxychloroquine outside of clinical trials. randomized to test effectiveness.

Arshad, S et al.¹³ published their observational, retrospective study, where they evaluated mortality in four groups: one group treated with hydroxychloroquine alone, another combined with azithromycin (but only for selected patients), another only with azithromycin and another with none of these drugs. Although they found a decrease in mortality in the group treated with hydroxychloroquine alone, it does not have statistical strength because it was not a randomized, blind and prospective trial. Additionally, 68% of patients received adjunct corticosteroid therapy and another 4.5% received anti-IL-6 tocilizumab.

Magagnoli, J et al.¹⁴ performed a retrospective analysis of hospitalized patient data with confirmed SARS-CoV-2 infection at all U.S. Veterans Health Administration Medical Centers. They evaluated death and the need for mechanical ventilation in patients medicated with hydroxychloroquine alone or associated with azithromycin and patients without treatment with these drugs. They found no evidence that the use of hydroxychloroquine, with or without azithromycin, reduced the risk of mechanical ventilation in hospitalized patients with Covid-19. On the other hand, they identified an association of increased general mortality in patients treated with hydroxychloroquine alone.

Lecronier, M et al.¹⁵ published their observational and retrospective study, in which no benefit of hydroxychloroquine or lopinavir/r could be demonstrated compared to standard treatment in ICU patients. They also found no-reduction in viral load between admission and day 7.

Paccoud, O et al.¹⁶ in their retrospective observational study, concluded that, in adults hospitalized with Covid-19, no significant reduction in the risk of unfavorable outcomes was observed with hydroxychloroquine compared to standard care.

Skipper, CP et al.¹⁷ published their randomized, double-blind, placebo-controlled trial in non-hospitalized patients with mild symptoms from Covid-19. Early treatment with hydroxychloroquine did not reduce the severity of symptoms in the 14-day control compared to placebo. Adverse reactions occurred in 43% of patients in the group receiving hydroxychloroquine vs 22% occurrence in the group receiving placebo.

Mitja, O et al.¹⁸ also saw no benefit from the early use of hydroxychloroquine in patients with COVID-19 and mild symptoms in their open-label, multicenter, randomized, controlled (non-placebo) trial (ongoing full publication).

Two drugs “had a promising environment” against SARS-CoV-2: remdesivir (GS-5734), an experimental drug for the treatment of Ebola virus infection, currently under evaluation in several trials and chloroquine or hydroxychloroquine, used since many years against malaria and autoimmune diseases, which continues to show a significant lack of efficacy.

The option of prescribing chloroquine or hydroxychloroquine for the treatment of patients with COVID-19 continues to be evaluated in several ongoing trials, where their toxicity is also being better evaluated.¹⁹ In addition, the scientific community has urged to report the results of the Trials that were conducted in China "as soon as they are available."

On the other hand, there is concern about the lack of reports of provisional results of ongoing trials.

In the USA, the Food and Drug Administration (FDA) authorized clinicians to prescribe hydroxychloroquine to patients admitted to the hospital with COVID-19, despite warnings from scientific advisers that no randomized, controlled trials have been conducted to support the safety and efficacy of these drugs in this population. This authorization for use in the emergency, as a result of a recent press conference by President Trump, who currently appears to continue self-medicating with this drug for pre or post-exposure prophylactic purposes, issued on march 28. The agency acknowledged that the approval was based on "anecdotal and limited in-vitro clinical data."²⁰

Currently, several clinical trials are underway including hydroxychloroquine, lopinavir/ritonavir, low-dose dexamethasone, azithromycin, tocilizumab, and plasma from convalescent Covid-19 donor patients.

F. Touret and X. de Lamballerie (Unité des Virus Emergents, UVE: Aix Marseille Univ), conclude that the results of ongoing trials (with various drugs) should preferably be reported in peer-reviewed publications, with detailed information, to enable the international scientific community to analyze the results, confirm in prospective trials the efficacy of the proposed treatment and thus guide future clinical practice.

This is essential and should be prospective, randomized and placebo-controlled trials, since there are few studies available with the necessary quality and scientific rigor that allow us to assess the "real benefit" or "harm" they may have on patients, both, hydroxychloroquine drug and others in current ongoing clinical trials.

References

_________________

Farmacología & Toxicología

Update julio 17, 2020

________________________________