Early Ambulatory Treatment for C19 – The Perspectives of Alain Maskens, MD, PhD, with a Foreword by Professor Peter A. McCullough

(Article also available in French)

Foreword by Professor Peter A. McCullough

This powerfully written, well researched, cogent summary of the principles of early ambulatory treatment of SARS-CoV-2 infection is sorely needed for Belgium, the EU, and many other countries that have failed to treat the disease early, before hospitalization. By not having early treatment, many countries have amassed catastrophic levels of fear, suffering, hospitalization, and death. Rapidly moving pandemics are not amenable to the slow and methodical nature of large (>20,000 patient) randomized placebo-controlled trials. To make matters worse, SARS-CoV-2 infection requires multiple medications from three or more therapeutic categories to be treated either at home or in the hospital.  There are no large, pivotal trials of three or more drug regimens in COVID-19.  Doctors waiting for “evidence” will forever be on the bench and not in the game. By treating patients early at home, there is reduced contamination, including to drivers, emergency personnel, and health care workers in clinics and hospitals.  Skilled doctors using combination regimens with alacrity reduce the intensity and duration of symptoms, and markedly reduce the risk of hospitalization and death.  Given the surge of COVID-19 and the slow arrival of still experimental vaccination, now more than ever a pivot to early ambulatory treatment is the public health move needed by populations bereft of appropriate and compassionate care that has been absent since the onset of the crisis.

Summary

There are currently treatments which, applied from the first symptoms of COVID-19, have a reasonable chance of reducing the severity and duration of the symptoms, and of reducing the risk of hospitalization, death, or even sequelae. These are mainly therapeutic regimens based on hydroxychloroquine or ivermectin. Numerous data published or in the process of being published do confirm this. Even if this effect were modest, applying only to a subset of the treated patients, it would already be of appreciable benefit for those patients themselves as well as for the hospital system. It could also help to reduce the course of the pandemic. Taken together, these effects could also accelerate the country’s full economic reopening, without having to wait for the availability of an effective vaccination coverage.

Conversely, no data shows that the benefit / risk balance of these treatments is unfavorable.

As doctors, faced with a patient at risk, can we satisfy ourselves just by waiting without any specific treatment for the possible onset of complications which will then require hospitalization and could lead to death, thereby losing opportunities of avoiding it? In view of the scientific data available, this wait-and-see attitude is no longer tenable. In the current context of the pandemic, it is important to implement these treatments widely and as quickly as possible. 

Introduction

During this second wave of the pandemic in Belgium, the care of non-hospitalized COVID-19 patients was more active than during the first. In nursing homes and at home, monitoring oximetry in at-risk patients has become common practice, and protocols involving the prescription of corticosteroids and anticoagulants have recently been proposed1. Despite this, the picture remained bleak. Hospitals and their intensive care units have again come under extreme pressure. The deaths peaked at over 200 per day, and their total number is approaching those in the first wave. Strict quasi-lock-down measures had to be imposed again. They entail a significant economic cost and severe psychosocial consequences. To date (January 14, 2021), the Belgian government is not in a position to lift them, and the risk of a third wave is now being mentioned.

How can the situation be improved, pending the large-scale administration of vaccines? Simply, by implementing a promising approach that has not yet been incorporated into our arsenal. It consists of giving at risk people early treatment, from the very first days of the onset of symptoms, with the aim of reducing the risk of aggravation. As we know, COVID-19 progresses in phases, starting with a viral upper airway infection with its classic symptomatology, followed in some patients by an extension of the infection to the lower respiratory tract (viral pneumonia). In some of them, finally, the viral stage will be followed by an intense inflammatory reaction (“cytokine storm”) complicated by reactions of intravascular thrombosis favored by disseminated endothelial damage. Any treatment active on the viral phase may reduce the risks of progressing to the inflammatory phase and its dramatic consequences. It will therefore prevent a number of hospitalizations and deaths. Another benefit is that such treatments could reduce the risk of sequelae. Finally, in the context of an epidemic thus made less fatal, restrictive containment measures could be relaxed more quickly.

Are there solutions available today for our at-risk patients? Many recent publications provide a positive answer to this question. They show the favorable effects on COVID-19 of molecules that have long been known for other indications, and therefore available and widely tested pharmacologically. We are talking about drug repurposing. What are these molecules? The best known are azithromycin, doxycycline, ivermectin and hydroxychloroquine. They can be used on an outpatient basis, and are safe if the protocols are followed correctly. 

Hydroxychloroquine-Based Treatments

Of these, hydroxychloroquine (HCQ) has been most extensively documented. Very active against the agent of malaria, but also endowed with anti-inflammatory and anti-viral effects, it was widely used in hospitals at the start of the pandemic, and several observational studies have shown fairly favorable results, particularly in Belgian2, Italian3, Spanish4, American5,5’ and Dutch6 hospitals, with a reduction in mortality of around 32%, 30%, 52%, 51%, 47%, or a reduction in ICU transfers of 53%, respectively, by comparison with the control cases. However, the lack of demonstrable effects in a few large randomized controlled trials (RCTs) caused the use of HCQ to be discontinued in this indication, most often to the benefit of dexamethasone. Note that these large trials involved patients with advanced stages of the disease.

In contrast, it is becoming increasingly clear that HCQ has a very real effect on the first phase of the disease, whether curative or preventive. Three RCTs dedicated to the treatment of COVID-19 patients in the early stages of the disease have been published to date. All show favorable results in terms of prevention of hospitalizations (reduction of 12%7, 25%8, and 52% 9 respectively in the number of hospitalizations compared with the controls). Taken individually, the results of these studies are not statistically significant, due to the insufficient number of observations. Indeed, they involved young and healthy patients, with therefore a limited number of hospitalizations even in the control groups. Thus, Skipper et al. observed “With placebo (194 patients), 10 hospitalizations occurred (2 non – COVID-19 – related), including 1 hospitalized death. With hydroxychloroquine (203 patients), 4 hospitalizations occurred plus 1 non-hospitalized death (P = 0.29) ”9. There is therefore a 3 in 10 possibility that this difference is due to randomness, and a 7 in 10 possibility that it is related to the effectiveness of the treatment. This positive trend is reinforced by the results of the other two RCTs, which are also favorable.

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It is also reinforced by the fact that the ten observational studies devoted to the same question and published to date after peer review all give favorable results, most often statistically significant even taken in isolation. The treatments studied were HCQ, alone13-17, in combination with azithromycin18-20 (AZ) or with AZ and zinc21,22 (Zn), applied from the early stages of the disease. The use of AZ in combination with HCQ is based on the observations of synergy between these two molecules both in vitro23 and in vivo24. The addition of zinc is based on the demonstration of the anti-viral effect of zinc and its enhancement by HCQ, which may facilitate its introduction into cells (“ionophore”) 25,26.

Of these ten studies, five present data on the risk of hospitalization, transfer to ICU and / or mortality: they all produce significantly positive results in favor of HCQ-based treatments. The other parameters observed are the duration of the persistence of the virus in the samples or of the persistence of symptoms. Here too, the data plead strongly for a favorable effect. Finally,  it is worth noting that the same applies to the five studies available in prepublication, but not yet peer reviewed at this stage27-31.

Among the studies cited above, those devoted to patients at risk (age, obesity, comorbidities) are the most instructive, insofar as hospitalizations and deaths are frequent in these patients in the absence of treatment: the possible effect of treatment can therefore be more clearly demonstrated. Two retrospective studies devoted to patients with COVID-19 treated early with HCQ + AZ in nursing homes showed a reduction in mortality down to 11.4% and 15.5% in the treated groups, whereas it was 61, 9% and 26.4% respectively in the control groups20,30. In the study by Lagier et al., the proportion of ICU transfers or deaths in patients over 60 years old was 5.0% in treated cases (HCQ + AZ) versus 17.6% in controls19. A fourth study (Derwand et al.)22 used a combination of HCQ + AZ + Zn in high-risk patients (age or co-morbidities) managed on an outpatient basis. Of the 141 patients treated, there were only 4 hospitalizations (2.8%) and 1 death (0.7%). In the control group (377 patients), these figures were 15.4% and 3.5% respectively, representing an 82% reduction in the risk of hospitalization, and a 79% reduction in the risk of death.

Of note, there are currently no published RCTs dedicated to the early treatment of patients at risk with HCQ alone or in combination, compared to a placebo. In view of the high probability of sequelae, hospitalization, or death in these patients when left without specific anti-COVID treatment, and in view of the data which accumulates on the favorable effects of the available treatments, the fact of giving patients at risk a placebo is becoming increasingly difficult to accept28.

In summary, without being a “miracle drug” against COVID-19, HCQ administered during the early stages of the disease is active in some of the patients treated, for whom it avoids disease progression, hospitalization and death.  In combination with azithromycin, or azithromycin and zinc, very encouraging results have been reported in patients at risk. The early start of treatment, from the very first days of the onset of symptoms, is a determining factor for success14,16,29,32-34. As for the possible cardiac toxicity of HCQ or regimens which incorporate this molecule, numerous data allow us to affirm that HCQ or these regimens are safe if they are applied in normal doses and according to the rules of the art in patients in the early stages of the disease. The authors of the eighteen studies mentioned above are unanimous on this point, on the basis of their own observations. In addition, studies  specifically dealing with the potential toxicity of HCQ as part of anti-COVID-19 treatments reach similar conclusions35-40. From his systematic review of the literature on this topic, Prodromos concludes: “Our literature search found that except for a few case reports of nonfatal adverse events, HCQ is actually consistently associated with a decreased incidence of cardiac adverse events and no cardiac mortality from torsades de pointe39.

Ivermectin-Based Treatments

Less known in the West, ivermectin (IVM) is widely prescribed in Africa and Asia to treat parasitic diseases such as lymphatic filariasis or onchocerciasis (river blindness). Its discovery earned William C. Campbell and Satoshi Ōmura the 2015 Nobel Prize in Medicine. Like HCQ, ivermectin has antiviral and anti-inflammatory properties, beyond its anti-parasitic action. Logically, it was from Asia and Africa that the first clinical studies devoted to the use of this molecule in COVID-19 came. But a completely fortuitous French observation also drew attention to ivermectin. In our regions, in fact, ivermectin is used for its effectiveness against scabies. This was the case in a nursing home where all the residents (median age: 90) as well as the staff received the drug as a preventive measure, following the appearance of a few cases of scabies in the institution. This occurred while the COVID-19 epidemic was active in the area. Compared with nursing homes in the same region, cases of COVID-19 were fewer and milder, with 0% mortality41.

Today, observations on the effectiveness of ivermectin in COVID-19 are piling up; they are extremely favorable as can be read in the systematic review published a few days ago on this subject by an international team coordinated by Paul Marik (US, UK, Norway)42. Regarding more specifically the effects of ivermectin on the early stages of COVID-19, data from 14 studies are currently available (three peer-reviewed, 11 in preprint), including eight randomized clinical trials (two have already been published after peer review, and six are in the process of being published)43-56. All studies involved a normal population (no selection of high risk patients), with mild to moderate symptomatic COVID-19, treated on an outpatient basis with ivermectin, often in combination with either azithromycin or doxycycline. Each of the 14 studies shows a strongly favorable effect, in the form of a decrease in the viral load and / or a faster or more frequent resolution of symptoms, and therefore a reduced risk of hospitalization.

The largest of the RCTs cited in the systematic review by Marik’s group42,52 involved 400 patients of which 363 completed the study. The percentage of patients showing clinical improvement on day 7 is higher in the treated group (IVM + AZI or doxycycline) compared to the control group (60.7% vs. 44.4%, p <.03). The proportion of patients progressing to clinical deterioration is two times lower in the treated group (8.7% vs 17.8%, p <.013). Since most cases were mild to moderate, there were only two deaths. Both were in the control group.

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The largest of the observational studies involved a consecutive series of 2688 patients, all treated with AZ + IVM. Only 16 patients had to be hospitalized, including 2 in ICU, and only one died.53 

Details of other studies of ivermectin treatment of early cases of COVID-19 are given in the systematic review cited above42.

These results are very promising. They are further reinforced by the fact that studies (observational and RCT) of IVM in the treatment of hospitalized COVID-19 cases also give very favorable results, and this in a statistically significant manner in most observations42. In his recent (12/27/2020) meta-analysis of the 11 peer-reviewed RCTs published on the efficacy of ivermectin at various stages of COVID-19 severity, for a total of 1452 patients, Hill observes, amongst other positive effects,  an improvement in survival rates of the order of 83% (95% CI: 65 – 92%) in the four RCTs which address this parameter57. Similarly, a favorable effect is also observed in studies on the preventive effect of ivermectin42. Finally, it should be noted that the toxicity of ivermectin is almost zero and its side effects are rare and not very marked. It has been used for nearly 40 years and billions of doses have been administered as part of parasitosis prevention campaigns58.

A comprehensive COVID-19 early therapy protocol

Both ivermectin and hydroxychloroquine are now included in the protocol proposed by a large international team of researchers and clinicians35,59. They recommend either one or the other medication, in combination with azithromycin or doxycycline:

They also insist on the close monitoring of patients and the implementation of medications adapted according to the evolution of the disease in each patient, in particular corticosteroids, anticoagulants and oxygen: “Multifaceted highly targeted sequential multidrug treatment”. This approach allowed them to dramatically reduce the need to hospitalize or the deaths, respectively 2.2% and 0.3% in a high-risk population (age> 50 years or presence of comorbidities)60.

Conclusions

There are currently treatments which, applied from the first symptoms of COVID-19, have a reasonable chance of reducing the severity and duration of the symptoms, and of reducing the risk of hospitalization, death, or even sequelae. Numerous data published or in the process of being published do confirm this. Even if this effect were modest, applying only to a subset of the treated patients, it would already be of appreciable benefit for those patients themselves as well as for the hospital system. It could also help to reduce the course of the pandemic61. Taken together, these effects could also accelerate the country’s full economic reopening, without having to wait for the availability of an effective vaccination coverage.

Conversely, no data shows that the benefit / risk balance of these treatments is unfavorable.

As doctors, faced with a patient at risk, can we satisfy ourselves just by waiting without any specific treatment for the possible onset of complications which will then require hospitalization and could lead to death, thereby losing opportunities of avoiding it? In view of the scientific data available, this wait-and-see attitude is no longer tenable. In the current context of the pandemic, it is important to implement these treatments widely and as quickly as possible. 

Three measures could support this action.

– Urgent attention must be given to ensure the availability of oral ivermectin in pharmacies in Belgium (currently ivermectin is only available as a skin cream in this country).

– In addition, general practitioners must be informed as soon as possible of these options, in order to be able to discuss them with those of their patients at risk who are starting COVID-19, and in order to implement the treatments if this option is chosen by their patients, in dialogue with them.

– Finally, it would be appropriate for the efforts of general practitioners to be supported by a national strategy for the early care of patients at risk. This support could include:

– constant monitoring to check the evolution of data on the available treatment options;

– a support activity documenting best practices in the implementation of treatment options,  and updating them as new data become available;

– the establishment of infrastructures allowing the effective implementation of these treatments in patients where conditions do not permit home monitoring and isolation.

Brussels, Januari 14, 2021

Alain P. Maskens, MD, PhD

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Efficacy of early hydroxychloroquine treatment in preventing COVID-19 pneumonia aggravation, the experience from Shanghai, China

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