HYDROXYCHLOROQUINE: IMPACT IN THE SECOND WAVE OF

COVID-19 IN BRAZIL

Vinícius E. Pimentel; Diana Mota Toro; Pedro Viera da Silva-Neto; Malena Martínez
Pérez; Carlos A. Sorgi.

ABSTRACT

Brazil lives in a state never seen before with COVID-19, which can even

become endemic in the country, which is why it requires international attention. The

Brazilian scientific community warns of a possible national collapse of the public health

and funeral system. But what was Brazil's mistake, even though it is a world reference

in immunizations and public health? Here we show that the incentive to use

Hydroxychloroquine and treatments that are not scientifically proven, coupled with the

lack of government leadership and the denial of the seriousness of the pandemic, made

the course of the disease take on the proportions that we live today. We would like to

create a discussion and a reflection about mistakes and successes in order to not repeat

again. In addition, the World Health Organization has asked the country to be serious

about how the pandemic is being conducted, as it is a worrying scenario.

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PERSPECTIVE - BRIEF COMMUNICATION

Since the beginning of coronavirus disease 2019 (Covid-19) pandemic, more

than 10 million people have been infected by severe acute respiratory syndrome

coronavirus 2 (SARS-CoV-2) in Brazil, with about 270,000 deaths reported to date 1.

Treatment with hydroxychloroquine sulfate has been recommended by the federal

government, resulting in a stock pileup of this drug adequate for 18 years of

consumption. The protocol established by the Brazilian Ministry of Health and

commonly used for the treatment of Covid-19 recommends the use of

hydroxychloroquine, either alone or in combination with ivermectin, nitazoxanide, and

azithromycin (drugs used as early treatment)2. Although most people were prescribed

this treatment in accordance with these protocols, the scientific community has warned

about possible lack of efficacy of these drugs in treatment of Covid-19.

In focus, chloroquine and its analog hydroxychloroquine, have low costs, are

easily accessible and widely used for the treatment of systemic lupus erythematosus and

malaria3. Due to its immunomodulatory effects and its success in preventing the

replication of SARS-CoV in vitro during trials in the latest SARS outbreak, it was

considered a therapeutic potential to be used against COVID-194.

Recently, the World Health Organization declared that hydroxychloroquine is

ineffective against COVID-195. The Brazilian federal government has earmarked funds

for the purchase and distribution of kits containing these drugs to the population, hoping

for their preventive benefits. The indiscriminate use of a potent antibiotic like

azithromycin by millions of people might lead to critical consequences like the

development of bacterial resistance and future outbreaks of infections. Moreover,

ivermectin and nitazoxanide used for the treatment of parasitic diseases cause liver and

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 6,7
neuronal damage when ingested at high doses over a long period . Interestingly, early

treatment was ineffective in preventing infections and even helped to increase the rates

of contamination of people who used it8.

Although no mechanism for the antiviral action in vivo of hydroxychloroquine

has been elucidated yet, it is believed that hydroxychloroquine can inhibit the entry of

the virus into the human cells by modifying the endosomal pH, preventing viral genetic

material from being released into the cytoplasm, and consequently impacting the viral

replication process, observed in vitro9. This drug can also interfere with the

glycosylation of angiotensin-converting enzyme 2 (ACE2)2, which is the cellular

receptor known to be the binding site of SARS-CoV-2 and associated gangliosides.

However, the results of different clinical trials to date did not support the use of

hydroxychloroquine, either alone or in combination with azithromycin as an antiviral

therapy for Covid-19, thus highlighting its possible ineffectiveness 7,10,11.

The possible lack of the protective effects of hydroxychloroquine might be a

consequence of its action on the endosomal pH, which would reduce the ability of the

endosomes to fuse with lysosomes. This is likely to prevent the degradation of viral

peptides, which is necessary for the presentation of SARS-CoV-2 antigens and

activation of adaptive immunity12. As consequence, inhibition of T-cell activation and

differentiation, low expression of co-stimulatory molecules, and changes in the levels of

cytokines produced by T and B cells might occur. This would compromise the T-cell-

dependent immune response and affect the ability to produce robust amounts of efficient

IgG antibodies, which are related to the generation of immune memory and protection

of the host against secondary infections. Additionally, changes in antigen presentation

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would impair the activation and response of cytotoxic CD8+ T lymphocytes against

intracellular pathogens 13.

Another mechanism described in the literature is that hydroxychloroquine might

inhibit the recognition of viral nucleic acids by toll-like receptors (TLRs). These

receptors are highly expressed in human B cells, and when stimulated, they control

inflammatory responses in the host through the production of antibodies, the release of

cytokines, and the presentation of antigens. It is known that therapeutic concentrations

of hydroxychloroquine inhibit the action of a subset of B cells called class-switched

IgD- CD27+ memory B cells, which produce large amounts of IgG 14.

Amid these circumstances, on December 10, 2020, the Brazilian government,

through the Ministry of Health’s National Health Surveillance Agency (ANVISA),

announced that a 55-year-old woman had been reinfected with a new strain of SARS-

CoV-2, raising an alarm throughout the Brazilian medical community. New cases of

SARS-CoV-2 reinfection are emerging, contributing to a worsening of the second wave

of Covid-19 in Brazil. This might be explained by the possibility of three different

phenomena 1) Infection of new patients who had never been infected by SARS-CoV-2;

2) Reinfection of patients already cured of Covid-19, but who due to previous treatment

with hydroxychloroquine might not have generated a robust humoral immune response

with the necessary amounts of neutralizing antibodies, and 3) Individuals who have

been infected or not by the original SARS-CoV-2 strain and who may be infected with

new virus variants recently reported in Manaus, United Kingdom and South Africa.

Mutations by these new variants are not yet well known, but it is already

described that they are highly contagious and potentially more lethal. Facts that can

negatively impact the protective effect of vaccines already developed to date and

causing collapses in the health system like what happened in Manaus, Brazil. These
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hypotheses outline a scenario that deserves the greatest attention from society as a

whole, especially from the Brazilian government.

Brazil is globally recognized for its largest and best national immunization

program for a country’s entire population. However, the public health policies created to

combat Covid-19 seem ineffective to avoid a possible collapse of both the Unified

Health System (SUS, the Brazilian public health system, considered the largest in the

world) and the private health systems. In an attempt to resolve these concerns, Brazilian

state governments have been looking for an efficient therapeutic strategy to combat the

disease and an immunization plan that addresses the peculiarities of each region of the

country.

The availability of Covid-19 vaccines in Brazil has raised questions about their

efficacy in persons previously treated with hydroxychloroquine and whether these

individuals’ immune system will be able to generate a long-term, neutralizing cellular

and humoral response against SARS-CoV-2 15.

Hence, it is important that more detailed studies are conducted to understand the

impact of hydroxychloroquine on the physiological behavior of the host immune system

in the face of reinfection. Moreover, it is important to understand whether there is likely

to be an adverse impact in the immune response generated by the vaccination against

Covid-19, since hydroxychloroquine has a half-life of about 1–2 months 13.

Combined efforts by the world's population and governments in creating public

politics will be decisive in successfully overcoming the Covid-19 pandemic and

preventing countless new deaths. Community thinking, rather than individualism, is the

priority.

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Acknowledgment

The authors thank health professionals and the entire scientific community
involved in combating the COVID-19 pandemic and contribute to the formation of
scientific knowledge. The authors would like to thank Prof. Lúcia Helena Faccioli,
Ph.D. support.

Authors' contributions

VEP, MMP, DMT, PVSN conceived the critical scenario hypothesis; they organized
the content, wrote the original draft and edited the final version of the manuscript and
performed a critical review of the manuscript. MMP and CAS coordinated all stages.
All authors have read and approved the final version of this manuscript.

Financial suppport

Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP): #2020/05207-6,

#2014/07125-6 and #2015/00658-1 and #2020/08534-8. Coordination for the
Improvement of Higher Educational Personnel (CAPES-Finance Code 001).

Conflicts of interest

The authors declare that they have no conflicts of interest