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Latin American Journal of Clinical Sciences and Medical Tecnology
Monday November 29th, 2021
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Bryan Nicolalde (0000-0002-7043-5515)a; Diego Añazco (0000-0003-1829-7001)a; Mariam Mushtaq (0000-0001-5929-3184)a; Ana Aguilar (0000-0001-7519-1583)b; Enrique Terán (0000-0001-6979-5655)b.
aUniversidad San Francisco de Quito, Colegio de Ciencias de la Salud, Quito, Ecuador; bUniversidad San Francisco de Quito, Colegio de Ciencias de la Salud e Instituto de Microbiología, Quito, Ecuador.
Corresponding Author: , . Tel: ; e-mail: eteran@usfq.edu.ec

Citation: Nicolalde B, Añazco D, Mushtaq M, Aguilar A, Terán E. Current Pharmacological Therapy against COVID-19: A Latin American Perspective.
Lat Am J Clin Sci Med Technol. 2020 May; 2: 59-68.
Received: April 20th, 2020.
Accepted: April 28th, 2020.
Published: May 11th, 2020.
Views: 2965
Downloads: 81
ABSTRACT

Introduction. SARS-CoV-2 infection is a public health emergency and several treatments against COVID-19 are in place while investigated simultaneously. Objective. To update on current pharmacological therapies against COVID-19, and its implications in Latin American countries. Methods. Publications on PubMed and in open access journals regarding pharmacological interventions against SARS-CoV-2 infection were reviewed, followed by analysis of the protocols already in place in Latin American countries. Results. Recent clinical data showed that lopinavir/ritonavir therapy was not effective against severe SARS-CoV-2 infection; however, further trials are underway and will help define the role of this therapy. Remdesivir showed significant efficacy in vitro, and clinical improvement in a report of compassionate-use, but data from controlled trials is not available currently. Tocilizumab plays an important role during cytokine storm, and studies revealed promising results. Chloroquine and hydroxychloroquine showed efficacy in vitro but clinical data are controversial, then further trials are needed to assess their role. Convalescent plasma, tocilizumab, lopinavir/ritonavir, chloroquine, and hydroxychloroquine have been approved by the Infectious Diseases Society of America (IDSA) and the Federal Drug Administration (FDA) in the context of clinical research. Various Latin American countries have already implemented antimicrobial therapy within their local protocols. Conclusions Promising agents, due to the emergency, are currently in some of the Latin American treatment protocols, although restricted to patients with non-favourable clinical course. Results from controlled clinical trials will be required to define the role of these drugs. Misuse and abuse of drugs can cause drug shortages if supply is not secured, and serious adverse effects might occur.

Keywords: treatment, COVID-19, SARS-CoV-2, Latin America
RESUMEN

Introducción. El COVID-19 es una emergencia de salud pública y actualmente diferentes tratamientos se encuentran investigándose simultáneamente. Objetivo. Realizar una revisión acerca de las terapias farmacológicas actuales frente al COVID-19 y las consecuencias del uso de estos fármacos en los países latinoamericanos. Métodos. Se revisaron y analizaron publicaciones en PubMed y en revistas de acceso abierto referentes a terapias farmacológicas en contra del SARS-CoV-2. Se revisaron y discutieron los protocolos farmacológicos propuestos por las diferentes autoridades de salud en países de Latinoamérica. Resultados. Ensayos recientes demostraron que la terapia con lopinavir/ritonavir no fue efectiva en infecciones severas por SARS-CoV-2; sin embargo, se requieren ensayos adicionales para definir la importancia de esta terapia. Remdesivir demostró eficacia in vitro e in vivo, pero aún no existen ensayos randomizados disponibles para demostrar su beneficio. La terapia con tocilizumab es crucial durante la tormenta de citocinas y estudios han demostrado resultados prometedores. La cloroquina y la hidroxicloroquina han demostrado eficacia in vivo, pero los datos clínicos generan controversia, por lo que se necesitan más estudios para poder determinar su importancia en el tratamiento de COVID-19. Entes como la Infectious Diseases Society of America (IDSA) y la Food and Drug Administration (FDA) han aprobado el uso de plasma de convaleciente, tocilizumab, lopinavir/ritonavir, cloroquina e hidroxicloroquina en el contexto de investigación clínica. En Latinoamérica, algunos países ya han implementado en sus guías de manejo algunos de estos medicamentos. Conclusiones. Aunque algunos agentes farmacológicos prometedores ya han sido incluidos en las guías de manejo local en Latinoamérica, únicamente se emplean cuando el cuadro clínico del paciente no es favorable. Actualmente no existen estudios aleatorizados que identifiquen a estas terapias como efectivas, pero varios estudios están en proceso. La falta de regulación que existen en algunos países en la venta de fármacos y la automedicación pueden representar un problema de desabastecimiento y potenciales efectos adversos.

Palabras clave: tratamiento, COVID-19, SARS-Cov-2, América Latina

INTRODUCTION

In December 2019, an outbreak of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. This infection has rapidly spread worldwide and in March 2020, the World Health Organization declared it as a pandemic.1 Mortality ranges from 1.8 to 3.4%.1 Several drugs have been proposed to be repurposed to treat coronavirus disease 2019 (COVID-19). Antivirals, antimalarials, immunomodulatory drugs, and recently convalescent plasma therapy have been regarded as promising options. This article reviews potential therapeutic options that have emerged and limitations that Latin American countries may face.

MATERIAL AND METHODS

In vitro and in vivo experiments, case reports, clinical trials, and review articles, as well as articles focusing on pharmacological interventions on other relevant infections, including SARS and MERS, were retrieved from PubMed and in open access journals. Keywords used also included “potential pharmacological interventions” and terms referring to “SARS-CoV-2”, “COVID-19”, “2019-nCOV”, and “Wuhan coronavirus”. Additional relevant articles were recommended by the senior authors, while clinical trials in progress were reviewed from clinicaltrials.gov. Due to rapidly emergent data, some pre-prints were assessed. Therapeutic protocols from Latin American countries, if publicly available, were obtained from the official website of the respective health authority. Countries lacking of an available local protocol, or countries that declared following WHO protocols were not included.

RESULTS

Review of Promising Therapeutic Interventions against COVID-19

The emergence and rapid spread of SARS-CoV-2 around the globe have motivated the search for drugs that may be potentially repurposed to improve clinical outcomes in patients with COVID-19. Some data available is a result of previous research on SARS-CoV and MERS-CoV, which belong to the same genera as SARS-CoV-2 (Betacoronavirus).2

Lopinavir/ritonavir

Lopinavir (LPV) is a protease inhibitor originally designed for HIV-1, while ritonavir (RTV) increases the serum concentration of LPV through inhibition of CYP3A-mediated degradation of LPV. Viral protease is an essential enzyme involved in the processing of polyproteins obtained from viral RNA translation. In vitro studies have shown that LPV/RTV therapy is effective against SARS-CoV and MERS-CoV.2 Likewise, there is favorable clinical evidence of its use in SARS from two retrospective matched cohort studies, especially if used during the early stage. The clinical evidence of LPV/RTV treatment in MERS is limited.

However, a recent open-label randomized controlled trial was conducted in 199 hospitalized patients with confirmed COVID-19 severe infection. Its objective was to assess the safety and efficacy of adding LPV/RTV (400-100 mg / BID for 14 days) to standard care (n=99).3 It failed to show a significant difference when compared to standard care alone (n=100) in terms of clinical improvement (hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.95 to 1.85; P=0,09) and 28-day mortality (19,2% vs 25%; risk difference [RD], -5.8%; 95%CI -17.3 to 5.7). Additionally, LPV/RTV failed to reduce the viral RNA load and duration of RNA detectability when compared to standard care alone.

Gastrointestinal adverse events (including four serious events) were more common in patients receiving LPV/RTV, and 14% of patients were unable to complete the full 14-day course. A posthoc subgroup analysis revealed that patients treated with LPV/RTV within 12 days after symptoms started did not have a reduction in time to clinical improvement (HR, 1.25; 95% CI, 0.77 to 2.05).

This trial had several limitations due to its urgent nature including lack of blinding, small sample size, and a small number of events. Nonetheless, it is unlikely that the use of LPV/RTV to be highly effective in hospitalized patients with COVID-19. Similarly, potential interactions with drugs used in critical care may further hinder its use. Additional research will be needed to evaluate the role of LPV-RTV in severe COVID-19.

Remdesivir

Remdesivir (RDV) is an adenosine analogue that causes premature termination of viral RNA chains during transcription. It has shown potent in vitro antiviral activity against multiple RNA viruses, including Ebola virus, MERS-CoV, and SARS-CoV. RDV has shown a superior in vitro and in vivo antiviral activity against MERS-CoV when compared to LPV/RTV. RDV was associated with a significant reduction in lung injury in mice models.4 Similar results were observed in a nonhuman primate (NHP) MERS model, in which both prophylactic and therapeutic RDV was associated with a reduction in viral replication, lung injuries and clinical signs.5 Data has shown that the EC90 value of RDV against SARS-CoV-2 in Vero E6 cells was 1,76 μM and that its working concentration is likely to be attained, based on previous NHP models.6

Grein and colleagues recently reported clinical outcomes from a cohort of 53 patients with severe COVID-19 receiving RDV under compassionate-use programs.7Improvement in oxygen-support status was observed in 68% of patients (n =36), whereas 15% (n = 8) worsened. Overall mortality was 13% (n=7), six of these patients were receiving invasive ventilation and one was receiving noninvasive support. Viral loads were not collected and RDV antiviral effects could not be assessed. The data of this report is severely limited, and interpretation regarding RDV effectivity should be made cautiously until results from multiple randomized clinical trials, currently in progress, become available. Importantly, at the time of this review, Gilead Sciences, Inc. has mentioned that they are working on accelerating manufacturing timelines and developing expanded access programs for compassionate-use in the United States and some countries in Europe.8For now, it is unlikely that RDV could be available in the short-term for Latin American countries.

Camostat Mesylate

The spike (S) protein of coronaviruses is essential for viral entry into cells. Cellular proteases cleave S protein, which permits the fusion of viral and cellular membranes. It has been shown that both SARS-CoV and SARS-CoV-2 use the angiotensin-converting enzyme 2 (ACE2) as an entry receptor, and the cellular transmembrane protease, serine 2 (TMPRSS2) for S protein priming. The use of a TMPRSS2 inhibitor (camostat mesylate), approved in Japan for an unrelated indication, effectively blocked SARS-CoV-2 infection of lung cells in vitro.9 Further in vivo studies and clinical evidence will be required, but the fact that this drug has already been approved for human use and its potential effect on blocking SARS-CoV-2 cell entry is promising.

Other Antivirals

Several antiviral drugs approved for other conditions are currently being studied, including umifenovir, favipiravir, oseltamivir, and ribavirin. Evidence is limited, but various clinical trials are underway and will help determine the efficacy and safety of using these drugs in COVID-19. Out of these, oseltamivir and ribavirin may be readily available in countries in Latin America. Nonetheless, their use for COVID-19 should not be encouraged. Oseltamivir is an agent designed for influenza, it exerts its effect by inhibiting neuraminidase, an enzyme that is not used by coronaviruses. There is no evidence to suggest that oseltamivir has in vitro activity against SARS-CoV-2. It may be useful in the context of empirical treatment for viral pneumonia before a specific etiology is determined. However, this drug should not be continued in patients with COVID-19 if influenza is ruled out. An important concern is that indiscriminate use of oseltamivir may cause drug shortages, and patients requiring it for influenza treatment may be highly affected.10 Ribavirin is a guanosine analogue that impairs RNA viral synthesis. Wang and colleagues recently showed that the in vitro effectivity of ribavirin against SARS-CoV-2 was poor when compared to remdesivir and chloroquine.6 Dosage that might be needed to exert an effect is risky due to increased toxicity and would outweigh potential benefits, so this agent is not a viable option.

Immunomodulatory Drugs

A cytokine storm may be present in severe COVID-19 and lead to significant complications, such as lung injury.11 Granulocyte-colony stimulating factor (G-CSF) and interleukin-6 (IL-6) were the principal cytokines detected in 21 severe to critical patients with COVID-19.12 Tocilizumab, an antihuman IL-6 receptor monoclonal antibody, has the capability of binding to membrane-bounded (MIL6R) and soluble IL-6 receptor (sIL6R) and has been proposed for patients with COVID-19. A study on 21 severely ill patients evaluated the use of tocilizumab in patients who were already receiving lopinavir, methylprednisolone, and other symptomatic relievers.11 Data showed clinical improvement, 19 patients (90.5%) were discharged, lymphocyte count and C-reactive protein values normalized, and lung injuries determined by CT improved. However, data is severely limited. The sample size was small, patients were treated with multiple drugs, and no control group was available to determine the effect of tocilizumab. Further clinical evidence will be required to determine whether tocilizumab improves clinical outcomes in patients with SARS-CoV-2 infection.

Interferons (IFNs) are also being studied. In preliminary results of unpublished data by Nezhad and colleagues, it was established that providing IFNs in very early stages of the disease could be an alternative treatment.13 Further research will be needed to define optimal timing and dose adjustment protocols; clinical data will be required to assess their safety and efficacy.

Chloroquine and Hydroxychloroquine

Chloroquine and hydroxychloroquine are antimalarial agents showing antiviral effects in both in vitro and in vivo experiments. Wang and colleagues reported that chloroquine had in vitro activity against SARS-CoV-2, with an EC50 and EC90 of 1.13 µM and 6.9 µM, respectively, at 48 hours.6 Further data showed that hydroxychloroquine had a superior in vitro antiviral effect (EC50: 0,72 µM) when compared to chloroquine (EC50: 5.47 µM).14

The mechanism of action by which chloroquine and hydroxychloroquine work is similar, but differences have been demonstrated at the cellular level. Both drugs are weak bases that raise the pH of organelles dependent on an acidic environment, such as lysosomes and endosomes. The basic intracellular environment interferes with the viral replication process.14–16 Both drugs can inhibit the conversion of endosomes to mature phagolysosomes. However, it was observed that the number and size of these phagolysosomes changed significantly with the use of hydroxychloroquine, but not with chloroquine.15 These morphological differences could explain the hydroxychloroquine superior in vitro effects. Additionally, chloroquine can alter glycosylation of the ACE2 receptor and spike proteins, interfering with viral entry into the cell.6,15,16

These drugs also have immunomodulatory effects. Many complications related to COVID-19 have been attributed to proinflammatory cytokines.11Elevations of TNF-α, IL-2, IL-7, macrophage chemoattractant protein 1 have been shown in severely-ill patients with COVID-19.17,18Increased IL-6 has been proposed as a prognostic factor among patients with COVID-19.19In vitro experiments revealed that altered intracellular pH due to chloroquine and hydroxychloroquine can alter TLR-9, TLR-7, and cGAS-STING signaling; processes that are essential for expression of proinflammatory cytokines. Furthermore, both drugs inhibit the production of IL-1, IL-6, and TNF-α by suppressing T-cell activation via MHC class II pathway.15–19

According to the physiologically-based pharmacokinetic models (PBPK), it was determined that hydroxychloroquine (loading dose of 400 mg; followed by 200 mg twice daily for 5 days) could achieve a concentration that is three times more potent than chloroquine (500 mg twice a day).14

Preliminary results of unpublished data suggested that the use of chloroquine may be superior to placebo since it could improve clinical and radiographic findings as well as reduce the time of clinical improvement.20 Remarkably, Gautret and colleagues recently conducted an open-label, non-randomized trial in which they compared the use of hydroxychloroquine alone (600 mg daily), hydroxychloroquine (600 mg daily) plus azithromycin (500 mg on the first day, and then 250 mg per day for next four days), and a control group in patients with confirmed COVID-19.21 Viral load was determined in nasopharyngeal swabs. It was found that on the sixth day of treatment with hydroxychloroquine, 70% of patients were virologically cured, compared with 12.5% in the control group (p=0.001). The six patients who were treated with hydroxychloroquine plus azithromycin were virologically cured. Even though this study had a small sample size (n=36), it was not blinded nor randomized and included only hospitalized patients, it is consistent with previous in vitro data.

An unpublished study collecting clinical data to emulate a target trial assessed the effect of using hydroxychloroquine in hospitalized patients requiring oxygen.22Primary endpoints included intensive care unit (ICU) transfer within 7 days of inclusion and/or mortality from any cause. Patients receiving hydroxychloroquine (n=84) had no significant improvement when compared to controls (n=97) in terms of ICU transfer and/or mortality (16 vs 21 total events; RR, 0.91; 95% CI, 0.47-1.80). Additionally, hydroxychloroquine was discontinued in 8 patients (9.5%) due to electrocardiographic abnormalities. However, this data has not been peer-reviewed and is severely limited due to a lack of randomization and potential confounders Randomized trials in progress will help settle the role of these drugs.

Obviously, side effects must be taken into consideration, particularly with concomitant use of azithromycin because of the possibility of fatal arrhythmias due to QT prolongation.19

Albeit in vitro data is promising, clinical data is not currently clear since data from well-controlled randomized clinical trials is not yet available, and the preliminary data are controversial, with some positive21,23,24 and negative22,25 data. Additionally, these drugs are attractive due to their low price and capability of widespread manufacturing, which is particularly important in low-resource settings. The role of these medications on prophylaxis for health care workers is currently being explored (see in clinicaltrials.gov, NCT 04308668).

Convalescent Plasma Therapy

FDA has recently approved the use of convalescent plasma for seriously ill patients with COVID-19.26 The use of convalescent plasma therapy is a type of passive immunity.27 This method has been used since the early 20th century for epidemics of polio, mumps, measles, and influenza.28 It was also used during the SARS outbreak in 2001. A trial showed that 80 patients with SARS who received passive immunity before day 14 were discharged from the hospital before day 22.29 Shen and colleagues treated 5 patients who developed acute respiratory distress syndrome (ARDS) due to SARS-CoV-2 with convalescent plasma.30 The results were promising, temperature normalized within 3 days in 4 out of 5 patients, SOFA scores decreased, and PAO2/FIO2 ratio increased within 12 days. SARS-CoV-2–specific neutralizing antibody titers increased and viral loads were negative within 12 days after the transfusion. ARDS resolved in 4 patients within 12 days, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Despite the limited number of patients, this data is promising.

Convalescent plasma is more effective when used in early infection. Antibodies work better by neutralizing a small inoculum and can also contribute with immunomodulatory effects.27–30Data suggest that the use of convalescent therapy reduces the viral load.31Based on these premises, the FDA has approved the use of convalescent therapy in critically ill patients with COVID-19. Requirements for the donation of serum include confirmed COVID-19 diagnosis virological cure of 14 days or longer, serum with the presence of neutralizing antibodies, and negative for HLA antibodies.26Although therapy has been approved for advanced stages of the disease, prior evidence shows that effectiveness may be superior when the viral load is minimal.27Therefore, predicting the risk for complications before they occur, and using convalescent plasma in the early stages of the disease could be more beneficial than using it in seriously-ill patients.

A major obstacle for some countries may be the limited number of patients who have recovered. Additionally, not every patient who recovers will produce neutralizing antibodies. Possible side effects include infections, serum sickness disease, and antibody-dependent enhanced infection.27 The risk of these adverse effects is low but must be considered.

Ivermectin

Recently, ivermectin, an approved antiparasitic drug, showed significant in vitro activity against SARS-CoV-2. When compared to control samples, the addition of ivermectin to infected Vero/Hslam cells resulted in the effective loss of essentially all viral material within 48 hours. The hypothesized mechanism is inhibition of nuclear import of viral proteins through importin (IMP) α/β1heterodimer.32 Clinical data will be needed before assessing the efficacy of ivermectin in COVID-19, even more after the caution notice recently published based on two letters to the editor of the journal.33–35

Antimicrobial Therapy and Latin American Reality

The burden of the disease in the region is highly variable. Some Latin American countries have implemented the use of specific drugs within their local protocols, while other countries chose supportive management alone due to the lack of enough evidence. Local protocols in Costa Rica, Panama, Nicaragua, Honduras, Guatemala, Cuba, Brazil, Mexico, and Bolivia do not endorse the use of any specific pharmacological therapy against COVID-19.36–43 In Argentina, Ecuador, Peru, and Colombia, local guidelines recommend the use of antiviral (lopinavir/ritonavir), antiparasitic (chloroquine/hydroxychloroquine), antibiotic (azithromycin), and immunomodulatory (tocilizumab/interferons) therapies depending on the severity of the case (Table 1). Ecuador also suggests the use of chloroquine and hydroxychloroquine as prophylactic agents in healthcare workers.44–47 In Brazil, the guidelines authorize the use of either chloroquine or hydroxychloroquine in confirmed cases and at the discretion of a doctor as adjunctive therapy in the treatment of severe cases in hospitalized patients.48

Table 1. Comparison of pharmacological therapy for COVID-19 in Latin American protocols
CountryHydroxychloroquine / ChloroquineLopinavir / ritonavirOseltamivirCorticosteroids

Argentina

Severe pneumonia: hydroxychloroquine 400 mg the first day and then 200 mg the following ten daysSevere patients: early treatment with Lopinavir/ritonavir 400 mg / 100 mg BID for 10-14 daysNo recommendation issuedNot recommended

Bolivia

Consider as adjunctive therapy in treatment of severe forms: hydroxychloroquine 800 mg first day and then 400 mg the next four days or chloroquine 900 mg first day and then 450 mg the next four daysNo recommendation issuedConsider in ARDS without established etiology. Suspend use if SARS-CoV-2 infection is confirmed by RT-PCRNot recommended unless
there is another indication for its use. No evidence of benefits in treatment of SARS-Cov-2

Chile

Moderate and severe forms of pneumonia: hydroxychloroquine 400 mg the first day and then 200 mg the following ten daysNo recommendation issuedNo recommendation issuedNot systematically recommended
unless presence of ARDS or septic shock. Treatment for 5-7 days

Colombia

Under medical
consideration
No recommendation issuedNo recommendation issuedNo recommendation issued

Costa Rica*

No recommendation issuedNo recommendation issuedNo recommendation issuedNot systematically recommended

Cuba

No recommendation issuedNo recommendation issuedNo recommendation issuedNo recommendation issued

Dominican Republic

No recommendation issuedNo recommendation issuedNo recommendation issuedNot systematically recommended
unless they are indicated for other reasons

Ecuador

Moderate pneumonia: chloroquine 500 mg BID the first day, and then 250 mg QD for 10 days; hydroxychloroquine 400 mg the first day and then 200 mg QD the following 10 daysSevere patients: Lopinavir/ritonavir 200 mg / 50 mg QD for 14 daysUntil ruling out influenzaNot recommended in early stages. Used in asthmatic patients or bronchial hyperreactivity exacerbation

Severe pneumonia: hydroxychloroquine 400 mg the first day and then 200 mg the following ten days in addition to azithromycin 500 QD for the next 5 days

Prophylaxis for health care workers: chloroquine 500 mg on the first day, 250 mg daily after

Guatemala*

No recommendation issuedNo recommendation issuedNo recommendation issuedNot systematically recommended

No recommendation issuedNo recommendation issuedNo recommendation issuedNot systematically recommended

Mexico

No recommendation issuedNo specific antiviral treatment recommended based on current evidenceConsider initial treatment in patients if influenza is suspected, regardless of vaccination statusNot indicated for SARS-CoV-2 infection

Nicaragua*

No recommendation issuedNo recommendation issuedNo recommendation issuedNot systematically recommended

Panama*

No recommendation issuedNo recommendation issuedNo recommendation issuedNot systematically recommended

Paraguay

Consider in severely-ill patients in critical care unit: chloroquine 500 mg BID for 5 daysNo specific antiviral treatment recommended based on current evidenceNot recommended unless influenza coinfection is present. May be considered on severely-ill patients: 150 mg QD for 5 daysNot systematically recommended in patients with viral pneumonia unless there is other indication for its use. Consider in severely-ill patients: methylprednisolone 40 BID for 5 days

Peru

Under medical consideration: chloroquine 500 mg BID for 7-10 days/ hydroxychloroquine 200 mg every 8 hours for 7-10 days/ hydroxychloroquine 200 mg TID for 7-10 days + azithromycin 500 mg first day and 250 mg QD for 5 daysNo recommendation issuedNo recommendation issuedNot systematically recommended unless there is other indication for its use

Uruguay

No recommendation issuedNo specific antiviral treatment recommended based
on current evidence
No recommendation issuedNot systematically recommended

Venezuela

Mild without comorbidities: Chloroquine 150 mg QDMild with comorbidities: lopinavir/ritonavir 200/50 mg plus IFN Alpha-2b QDNo recommendation issuedNot systematically recommended
in patients with viral pneumonia or ARDS, unless there is other indication for its use

Moderate or Severe: chloroquine 150 mg QD plus lopinavir/ritonavir 200/50 mg QD plus IFN Alpha-2b QD

ACEI: angiotensin converting enzyme inhibitors, ARB: angiotensin II receptor blocker, ARDS: acute respiratory distress syndrome, NSAID: non-steroidal-anti-inflammatory drugs, RT-PCR: reverse transcription polymerase chain reaction. QD: once daily, BID: every 12 hours, TID: every 8 hours. * Countries adhered to the Pan American Health Organization/World Health Organization guidelines

Comparatively, most Latin American protocols are similar to those previously used in Asia and Europe. The therapeutic use of antimicrobial therapy is restricted to groups with an unfavorable clinical course. However, it is remarkable to realize that most pharmacological therapies exert their optimal effect during the viral replicative phase. Chloroquine prevents phage-lysosome-dependent replication, as well as lopinavir/ritonavir therapy inhibits protease and thereby impedes the release of mature viral products.3,15 Additionally, convalescent plasma could be more effective against small viral inoculum.27 Nonetheless, experimental therapies such as remdesivir or camostat mesylate are not currently available in Latin America.

Recently, the Infectious Diseases Society of America (IDSA) approved the use of chloroquine, hydroxychloroquine, LPV/RTV, azithromycin, tocilizumab, and convalescent plasma therapy in the context of clinical trials.49The Federal Drug Administration (FDA) has also approved the use of chloroquine, hydroxychloroquine, remdesevir, and convalescent plasma therapy for emergency use.50The WHO has not approved any type of specific therapy yet (Table 2).51Under this premise, Latin American countries should promote research of specifically directed therapies against COVID-19, and collaborations from multiple countries in the region could provide valuable data regarding the safety and efficacy of using these therapies in a regional context.

Table 2. Comparison of approved pharmacological treatments by the FDA, IDSA or WHO
Organizations
Pharmacological treatmentFDAIDSAWHO

Convalescent plasmaYesYesNo

Chloroquine/HydroxychloroquineYesYesNo

RemdesivirYesNoNo

Lopinavir/RitonavirYesYesNo

TocilizumabNoYesNo

FDA: Food and Drug Administration; IDSA: Infectious Diseases Society of American Guidelines; WHO: World Health Organization43-45

These drugs could have multiple side effects or pharmacological interactions. In the context of emergency use of repurposed drugs, ethical concerns may arise. In some cases, it is hard to assess whether negative clinical outcomes are due to the disease process solely or due to potential side effects. For example, patients with COVID-19 may have neutropenia as a result of the infection, but patients receiving LPV/RTV may also develop neutropenia. The same doubt may arise in potentially fatal complications, such as cardiac arrhythmias, that could be induced by chloroquine and hydroxychloroquine.19,52 Therefore, it is necessary to consider risks and benefits when introducing these therapies within countries' protocols.

Likewise, the unregulated sale of drugs could be an important issue in Latin American countries. As mentioned before, these drugs were originally designed for other diseases, so inappropriate excessive use, if supply is not secured, may cause shortages and affect patients requiring these drugs chronically. Furthermore, indiscriminate use by population without medical supervision poses the risk of serious side effects.53

The use of convalescent plasma therapy has been approved for emergency use by the FDA, and it should also be considered by countries in the region. According to Casadevall and colleagues, a country must have six conditions to deploy convalescent serum programs for COVID-1927:

  1. Availability of a population of donors who have recovered from the disease and can donate convalescent serum.
  2. Blood banking facilities to process the serum donations.
  3. Availability of assays, including serological ones, to detect SARS-CoV-2 in serum and virological assays to measure viral neutralization.
  4. Virology laboratory support to perform these assays.
  5. Prophylaxis and therapeutic protocols, which should ideally include randomized clinical trials to assess the efficacy of any intervention and measure immune responses.
  6. Regulatory compliance, including institutional review board approval, which may vary depending on location.


None of the Latin American protocols has officially implemented the use of convalescent plasma, but it seems a promising therapy that could be readily applied in the countries of the region that are highly affected. However, the recovery rate must be considered, and if the total number of recovered patients is not enough, this therapy might not be plausible.

CONCLUSIONS

COVID-19 is a global health problem. Multiple in vitro, in vivo, and clinical trials are being conducted to find potential therapeutic options. Despite favorable evidence on LPV/RTV against SARS and MERS, recent clinical data showed that these drugs were not effective in patients with severe COVID-19 pneumonia; however, additional trials are underway to help to define its role against SARS-CoV-2 infection.

Remdesivir is a promising agent against COVID-19 due to its in vitro activity and a recent report of its compassionate use but further clinical data will be needed and the drug probably will not be readily accessible for countries in the region. Cytokine storm is critical in COVID-19 pathogenesis and tocilizumab seems promising, even so, further clinical data is also required.

Chloroquine and hydroxychloroquine are promising agents due to their price and the possibility of being manufactured extensively. Both in vitro and in vivo data showed favorable results with these medications. Hydroxychloroquine was superior in in vitro experiments. Several clinical trials are underway to assess their efficacy, and many countries have implemented these drugs within their protocols. Nevertheless, side effects profile, drug interactions, and shortage concerns should be considered. Convalescent plasma therapy is also attractive, but one of the main current restraints is that donors may be limited in some countries.

As it was shown, most of the Latin American treatment protocols are similar to those used in Asia and Europe, and targeted therapy is restricted to patients with non-favorable clinical course. Drug repurposing without appropriate clinical data is controversial, and certain implications should be regarded in the Latin American region. Access to these drugs without medical supervision could lead to potentially fatal side effects, and if supply is not guaranteed, shortages could affect patients that need these drugs chronically. Regional governments must work on establishing strict guidelines for the use of these drugs, and pharmacovigilance should be promoted. Finally, the WHO announced the SOLIDARITY trial, a multinational effort across the globe to test four different drugs or combinations, including remdesivir, LPV/RTV, LPV/RTV, interferon beta, and chloroquine or hydroxychloroquine54; and its results will certainly help settle the role of these drugs in COVID-19 treatment.

CONFLICT OF INTEREST

None of the authors has anything to declare.

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Latin American Journal of Clinical Sciences and Medical Technology, Año 1, No. 1, octubre, 2019 es una publicación contínua editada por Vesalio S.C.; http://www.lajclinsci.com/    Editor responsable: Gilberto Castañeda Hernández.    Reserva de Derechos al Uso Exclusivo: 04-2019-062013242000-203; ISSN: 2683-2291; ambos otorgados por el Instituto Nacional del Derecho de Autor.    Responsable de la última actualización de este número, Web Master Hunahpú Velázquez Martínez, calle San Luis Potosí # 182-1, Col. Roma, Alcaldía Cuauhtémoc, C.P. 06700, Ciudad de México; teléfono: 55 64 40 41    Fecha de última modificación, 30 de marzo de 2020.
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All Rights Reserved® 2019

Latin American Journal of Clinical Sciences and Medical Technology, Año 1, No. 1, octubre, 2019 es una publicación contínua editada por Vesalio S.C.; http://www.lajclinsci.com/    Editor responsable: Gilberto Castañeda Hernández.    Reserva de Derechos al Uso Exclusivo: 04-2019-062013242000-203; ISSN: 2683-2291; ambos otorgados por el Instituto Nacional del Derecho de Autor.    Responsable de la última actualización de este número, Web Master Hunahpú Velázquez Martínez, calle San Luis Potosí # 182-1, Col. Roma, Alcaldía Cuauhtémoc, C.P. 06700, Ciudad de México; teléfono: 55 64 40 41    Fecha de última modificación, 30 de marzo de 2020.