Artigos

Conteúdo (article):

Pharmacological therapies for patients with human coronavirus infections: a rapid systematic review

Keitty Regina Cordeiro de Andrade – Andrade, Keitty Regina Cordeiro de -
- Ministério da Saúde - Departamento de Ciência e Tecnologia – keitty.andrade@saude.gov.br -
ORCID: https://orcid.org/0000-0002-8882-6856

Viviane Karoline da Silva Carvalho – Carvalho, Viviane Karoline da Silva - Ministério da Saúde - Departamento de Ciência e Tecnologia – viviane.carvalho@saude.gov.br
ORCID: https://orcid.org/0000-0002-6804-2333

Cecília Menezes Farinasso – Farinasso, Cecília Menezes - Ministério da Saúde - Departamento de Ciência e Tecnologia - cecilia.farinasso@saude.gov.br
ORCID: https://orcid.org/0000-0002-3612-4422

Aurelina Aguiar de Lima – Lima, Aurelina Aguiar de – Ministério da Saúde - aurelina@saude.gov.br –
ORCID: https://orcid.org/0000-0002-6240-1067

Roberta Borges Silva – Silva, Roberta Borges - Ministério da Saúde - Departamento de Ciência e Tecnologia - roberta.silva@saude.gov.br
ORCID: https://orcid.org/0000-0001-7273-5151

Virginia Kagure Wachira – Wachira, Virginia Kagure - Ministério da Saúde - Departamento de Ciência e Tecnologia - virginia.wachira@saude.gov.br
ORCID: https://orcid.org/0000-0001-8018-9939

Helaine Carneiro Capucho – Capucho, Helaine Carneiro - Universidade de Brasília - Departamento de Farmácia - helainecapucho@yahoo.com.br
ORCID: https://orcid.org/0000-0002-5438-7963

Patricia Medeiros de Souza – Medeiros de Souza, Patricia - Universidade de Brasília - Departamento de Farmácia - pmedeirossouza@uol.com.br
ORCID: https://orcid.org/0000-0003-4022-9187

Tazio Vanni – Vanni, Tazio - Ministério da Saúde - Departamento de Ciência e Tecnologia - taziovanni@gmail.com
ORCID: https://orcid.org/0000-0003-0398-9814

Camile Giaretta Sachetti – Sachetti, Camile Giaretta - Ministério da Saúde - Departamento de Ciência e Tecnologia - camile.sachetti@saude.gov.br
ORCID: https://orcid.org/0000-0003-1556-8339

Daniela Fortunato Rêgo – Rêgo, Daniela Fortunato - Ministério da Saúde - Departamento de Ciência e Tecnologia - daniela.rego@saude.gov.br
ORCID: https://orcid.org/0000-0003-1935-2201

RESUMO
O objetivo deste trabalho foi avaliar efeitos de tratamentos medicamentosos para infecções por Coronavírus. Trata-se de revisão sistemática rápida com buscas até 21 de abril de 2020 nas bases MEDLINE, EMBASE, Biblioteca Cochrane, BVS, Global Index Medicus, Medrix, bioRxiv, Clinicaltrials.gov e International Clinical Trials Registry Platform. Foram incluídos 36 estudos com 2.545 pacientes avaliando alternativas medicamentosas contra SARS, SARS-CoV-2 e MERS. A maioria dos estudos incluídos foi conduzida na China com delineamento observacional para tratamento da COVID-19. Dentre os tratamentos mais estudados estão antimaláricos e antivirais. Na terapia com antimaláricos, a metanálise de dois estudos com 180 participantes não identificou benefício da hidroxicloroquina em relação à negativação da carga viral via reação em cadeia de polimerase em tempo real e o uso de antivirais comparado ao cuidado padrão foi similar em relação aos desfechos. As evidências científicas disponíveis são preliminares e de baixa qualidade metodológica, o que sugere cautela na interpretação dos seus resultados. Pesquisas que avaliem a eficácia comparativa em ensaios clínicos randomizados, controlados, com tempo de acompanhamento adequado e com os métodos devidamente divulgados e sujeitos à revisão científica por pares são necessárias. Recomenda-se atualização periódica da presente revisão.
Palavras-chave: Coronavírus; Infecções por Coronavírus; Síndrome Respiratória Aguda Grave; Terapêutica; Revisão Sistemática.

ABSTRACT
This work aimed to evaluate the effects of drug therapies for coronavirus infections. This is a rapid systematic review with search performed until April 21, 2020 in the MEDLINE, EMBASE, Cochrane Library, BVS, Global Index Medicus, Medrix, bioRxiv, Clinicaltrials.gov and International Clinical Trials Registry Platform databases. Thirty-six studies with 2,545 patients evaluating alternative drugs against SARS, SARS-CoV-2 and MERS were included. Most of the included studies were conducted in China with an observational design for the treatment of COVID-19. Among the most studied treatments are with antimalarials and antivirals. In antimalarial therapy, the meta-analysis of two studies with 180 participants did not identify the benefit of hydroxychloroquine concerning the negative viral load via real-time polymerase chain reaction, and the use of antivirals compared to standard care was similar regarding outcomes. The available scientific evidence is preliminary and of low methodological quality, which suggests caution when interpreting its results. Research that evaluates comparative efficacy in randomized, controlled clinical trials, with adequate follow-up time and with the methods properly disclosed and subject to scientific peer review is required. A periodic update of this review is recommended.
Keywords: Coronavirus; Coronavirus Infections; Severe Acute Respiratory Syndrome. Therapeutics; Systematic Review.

INTRODUCTION
The outbreak of pneumonia cases, which initially occurred in Hubei, China, evolved into the 2019 Coronavirus Disease pandemic (COVID-19)1. The disease is caused by the Coronavirus-2 of severe acute respiratory syndrome (SARS-CoV-2)2. The World Health Organization (WHO) has declared strategic objectives on the pandemic, among them responding to critical knowledge gaps about the therapeutic options2 available for coronavirus infections.
Understanding the complete natural history of COVID-19 is evolving. The WHO3 published the provisional guidelines. In the clinical presentation, pneumonia seems to be the most severe frequent manifestation of the infection, characterized mainly by fever, dry cough, dyspnea, and bilateral infiltrates in chest imaging tests4-7. As of April 2020, there no vaccines or specific treatments were available for human coronavirus infections.
Given the developing coronavirus situation, policymakers urgently require a synthesis of evidence to make decisions and guide the population. Rapid evidence synthesis is recommended by WHO8 in circumstances like these. Thus, this study aims to evaluate the effects of drug therapies for coronavirus infections.
METHODS
Design and protocol registration
A quick, systematic review of the literature was carried out, a secondary study that gathers the available evidence on a topic, carried out swiftly, to meet the decision-makers\' demand in a timely fashion9. The study was conducted to scientifically and impartially inform the decision-making in the health of managers of the Brazilian Ministry of Health in the context of the public health emergency of national importance, COVID-19. The study protocol was submitted to the International Prospective Register of Systematic Reviews (PROSPERO) platform, but has not yet been evaluated. The report of this review is in line with the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Supplementary Table 1). This review is registered in "PROSPERO", registration number: CRD42020182351.
Eligibility criteria
Studies of systematic reviews, randomized clinical trials, cohorts, case-controls, and case series that evaluated the effects of alternative drug therapies for infection by any type of human coronavirus were included. We excluded studies that contained data that could not be extracted completely, overlapping data between studies, book chapters, letters to the editor, posters, editorials, modeling, guidelines or country guides, studies carried out on animals, or in silico.
Information sources and search strategies
A bibliographic search was performed in the sources of Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Cochrane Library, and Virtual Health Library (BVS). The lists of bibliographic references of the relevant studies were examined to identify possible eligible studies. A search was also conducted on the Global Index Medicus, Medrix, and bioRxiv, as well as free search on the websites of the governments of countries with confirmed cases and clinical trial, records through the Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP) databases. There were no restrictions on the participants’ age, language, status, and year of publication.
The search was updated until April 21, 2020. The search strategy was developed by one researcher and independently reviewed by another researcher. The strategies for each database are reported in a supplementary file (Supplementary Table 2).
Data collection process
The Rayyan system10 was adopted for the selection of studies and data extraction. After removing duplicate records, two reviewers independently selected paper by title and abstract, as per pre-defined eligibility criteria. The selected works were independently read in full by two authors. In both stages, any case disagreement was resolved by a third reviewer. The following data were extracted: author, year of publication, country, study design, age (mean years), type of coronavirus, sample size, proportion of men (%), funding sources, intervention, comparator, and (clinical, laboratory) outcomes.
Methodological quality assessment
The evaluation of the methodological quality and the risk of bias of the included studies was carried out independently by six researchers, using appropriate tools for each study design, as follows: a) systematic reviews: A MeaSurement Tool to Assess Reviews (AMSTAR 2)11; b) randomized clinical trial: Cochrane bias risk assessment9; c) cohort and case series: Joanna Briggs Institute tools12.
Summary of results and statistical analysis
The outcomes assessed in this review were mortality rate, clinical outcomes (length of hospital stay, length of ICU stay, need for non-invasive mechanical ventilation, need for oxygen therapy, adverse events, body temperature), and detection of viral RNA (RT-PCR). The results of the included studies were presented descriptively. Data on outcomes evaluated by the included studies were reported considering the size of effect estimates (relative risk, absolute risk difference, odds ratio, the number required to treat, and others) and their respective confidence and variance measures (a measure of dispersion, confidence intervals, and p-values).
Due to the limited number of studies reporting similar results for infections, the meta-analysis was conducted only for two studies on hydroxychloroquine against SARS-CoV-2. A meta-analysis using the Mantel-Hazel method for dichotomous data with the random-effects model was chosen a priori. Risk ratio (RR) was used for timely estimation together with the 95% confidence interval. The chi-square test was applied to measure heterogeneity between studies with a significance level of p<0.05. The magnitude of the inconsistency was measured using the I-square (I2) statistics. High heterogeneity was considered when I2 was above 75%, moderate when it was between 55% and 75%, and low when I2 was below 25%. RevMan version 5.3 was used for the analysis.
RESULTS
Selection of studies
We identified 2,259 records, of which 91 were duplicated. After screening titles and abstracts, 68 records were selected for full-text reading. Of these, 36 met the eligibility criteria and were included in this review. The details of the selection process are illustrated in Figure 1, and the excluded studies and their respective reasons are described in Supplementary Table 3.
Main characteristics of the included studies
The main characteristics of the included studies are shown in Table 1. Most of the 36 included studies were retrospective cohorts and conducted in China, and published between 2018 and 2020. The mean age of patients was 48 years, and most of these people were diagnosed with SARS-CoV-2 infection or severe acute coronavirus syndrome (SARS-CoV) through real-time polymerase chain reaction (RT-PCR). Studies with patients with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) were also included. The effects of coronavirus drug therapies are described in Table 2.
Antimalarials
Four randomized controlled trials (RCTs)13-16, two retrospective cohorts17,18, a prospective cohort19, and three case series20-22 evaluated the use of hydroxychloroquine (HCQ) or chloroquine (CQ) for SARS-CoV-2. Four studies compared HCQ with standard treatment13,14,16,19. Three studies evaluated the time to clinical improvement13,14,16. In one RCT13, the time to normalize body temperature was similar between the groups, while treatment with HCQ resulted in less time in two other RCTs14,16. In a single study14, the number of days of cough was significantly less in the HCQ group. Two RCTs14,16 evaluated the negative viral load by RT-PCR on the seventh day after starting therapy. The meta-analysis found no significant difference in the probability of negative viral load by RT-PCR between the HCQ group and the group that received conventional treatment (RR=0.94; 95% CI: 0.78-1.13; 180 participants; I2=0%) (Figure 2). Moreover, a cohort19 had a significantly lower proportion of patients with negative RT-PCR in the HCQ group. A cohort18 showed that the HCQ group has a higher risk of death from any cause when compared to the group without HCQ. However, another cohort17 found no difference between the groups.
Five studies investigated the effects of HCQ associated with azithromycin (AZT) compared to standard treatment17-21. In a cohort19, the proportion of patients with negative RT-PCR was significantly lower in the HCQ group. On the other hand, the therapeutic combination had no significant effect in case series20. Another case series21 with 80 participants evidenced a negative virological result in 83% of patients who used HCQ on day 7 of follow-up, and in 93% on day 8. The mortality rate was assessed in two cohorts. In the first one18, it was worse in the group treated with HCQ and AZT, and in the other17, no differences were observed between groups. In one of the case series21, patients had nausea, vomiting, diarrhea, and blurred vision. In two other case series20,22, patients had persistent QT interval prolongation.
An RCT15 compared the use of CQ administered at different dosages. Preliminary results suggest that the high-dose QC regimen (12g administered over 10 days) was not safe. The authors canceled the tests when they found that one quarter of the patients tested with a high-dose of QC showed persistent QT prolongation above 500ms and higher lethality.
Antivirals and Antiretrovirals
Two clinical trials23,24 and one case series25 that reported treatments with lopinavir/ritonavir, arbidol (umifenovir), and interferon-α2b, were included. Most of the studies were conducted in China (n=2), and all targeted SARS-CoV-2. One of the studies compared the use of lopinavir (associated with ritonavir) with arbidol (umifenovir) and standard treatment without antivirals23. The rate of negative SARS-CoV-2 viral load after seven days was 35.3% for the group that took lopinavir/ritonavir, 37.1% for the group that received arbidol, and 41.2% for the group that did not receive antiviral therapy23. Patients who received lopinavir/ritonavir associated with standard treatment had fewer days of hospitalization (6 days) than the group that received only standard treatment (11 days)24. Adverse events were also lower among the group that received the intervention (19 events in the intervention group versus 32 events in the control group)24.
Immunomodulators
In a retrospective cohort26 conducted in China, viral clearance took about eight days (IQR: 5.5-15.5) between the group that received nebulized interferon-α2b and 6.5 days (IQR: 3.0-10.0) for the group that received interferon associated with arbidol26. The group that received only arbidol took about 10 days (IQR: 4.5-19.5) for viral clearance26.
Anticoagulants
Negri et al27 evaluated the use of heparin for the treatment of COVID-19 in a hospital in São Paulo, Brazil. The PaO2/FiO2 oxygenation index was evaluated before and after 72 hours of treatment, besides the duration of hospitalization and mechanical ventilation. The PaO2/FiO2 ratio improved from 254 to 325 (p=0.013), the mean hospital stay was 7.3, and the mean duration of mechanical ventilation was 10.327. Another study28 evaluated heparin use in the treatment of COVID-19 through negative viral outcomes, coagulation parameters, the concentration of C-reactive protein and inflammatory cytokines, number of lymphocytes before and after treatment. There was no significant difference between the two groups, except for an increase in IL-6 and in lymphocytes in the intervention group. The authors pointed out that heparin improves coagulation dysfunction, has anti-inflammatory effects, and can be used as a treatment for COVID-1928.
Corticoids
Four retrospective cohorts29-32 reported corticosteroid therapies. Two were performed in China, focusing on the SARS-CoV-230,31 coronavirus. The time to symptom improvement was assessed and was shorter in the group that received methylprednisolone (2.06 days) than in the group that did not receive treatment (5.29 days)30. One study showed a higher mortality rate for patients with COVID-19 who received corticosteroids (39%) than in the group of patients who did not receive them (16%; p=0.09)31. In patients with MERS-CoV, the mortality rate (74.2% versus 57.6%) and the need for invasive mechanical ventilation (93.4% versus 76.6%) were higher in the group receiving corticosteroids than in the group control group29. SARS-CoV patients who received corticosteroids were 20.7 times more likely (OR=20.7; 95% CI: 1.3-338) to be admitted to the ICU or die than those who did not use corticosteroids32.
Combined therapies
Bian et al.33 evaluated the efficacy of meplazumab, an anti-CD147 antibody, as a complementary therapy in patients with COVID-19 in China. Other associated treatments were antiretroviral (lopinavir/ritonavir), immunomodulator (recombinant interferon α-2b), glucocorticoid, and antibiotic (not specified) drugs. The control group did not receive meplazumab. In the intervention group, 94% of patients (p=0.006) were discharged from the hospital, and the median for the negative viral load was three days, with an increased C-reactive protein in 82.4% of cases. The reported adverse effects were only 2 cases that had elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and the condition was reversed after seven days. The researchers reported that this increase in transaminases was not associated with the use of meplazumab, as the same effect was observed in the control group33.
In another study31, treatment with corticosteroids (methylprednisolone, dexamethasone, and hydrocortisone) associated with antivirals (oseltamivir, arbidol, ganciclovir, interferon-α) and antiretrovirals (lopinavir/ritonavir) was compared with a group that received the same treatment, without corticosteroids. No difference was observed between the groups (adjusted OR=1.05; 95% CI: -1.92 to 2.01, p>0.3)31 in the mortality outcome after 28 days of hospitalization.
In yet another study34, treatment with interferon associated with ribavirin was evaluated, compared with the use of a support measure for the treatment of MERS. There was a need for mechanical ventilation in 76% of patients in the intervention group compared with 90% in the control group. The adverse effects reported in the intervention group were elevation of pancreatic enzymes and hemolysis, present in 3 patients34.
Chiou et al.35 evaluated a therapy with an antiviral (ribavirin) associated with corticosteroids (methylprednisolone, prednisone) for the treatment of COVID-19 compared with a regimen without ribavirin. An improvement in the chest image’s infiltrations was reported by 71% of the patients who received ribavirin compared to the control group (67%, p=0.05)35.
A study36 compared the use of antiretrovirals (lopinavir/ritonavir), corticosteroids, antibiotics, and supportive treatment vis-à-vis a similar treatment, but without lopinavir/ritonavir. The time to viral clearance had a median of 22 days compared to 28.5 in the control group. Moreover, the median hospital stay was 23 days compared to 18.5 in the control group36.
Methodological quality assessment
In general, the methodological quality of the included studies was moderate. The main limitations of the included randomized clinical trials were lack of allocation secrecy, blinding, and sample size of fewer than 100 participants. The primary limitations observed in the systematic reviews were related to the authors’ clarity regarding the process of assessing the risk of bias in the included studies, lack of description of eligibility criteria, and discussion about the heterogeneity in the findings. The included cohort studies were unclear as to the information about the control of confounding variables, length of follow-up, and patient eligibility criteria, besides the lack of comparable groups. Case series did not adequately describe patient eligibility criteria, demographic characteristics, and clinical data. No study was excluded because of its methodological quality. The critical assessment of the individual quality of each study is found in Supplementary Tables 4-7.
DISCUSSION
This review identified three systematic reviews, eight randomized clinical trials, 18 cohorts, and seven case series, with 2,545 patients, evaluating different drug alternatives to human coronavirus, who reported mortality in 14 days, a progression of lung lesions on computed tomography, clinical improvement, absence of viral detection in RT-PCR and adverse events. Antivirals and antimalarials were among the most studied therapies.
When there are no clinically proven treatments during epidemics, the tendency is to use drugs based on in vitro activity or observational studies. However, effective drugs based on in vitro studies and observational studies for other diseases were later proven to be ineffective in clinical trials37.
CQ and HCQ showed in vitro inhibitory effects on coronavirus infections38,39. As a known antimalarial and anti-autoimmune agent, HCQ appears to block infection by the SARS-CoV virus, increasing the endosomal pH required for membrane fusion between the virus and the host cell40,41. Furthermore, it has been shown to specifically inhibit SARS-CoV-2 replication by interfering with the glycosylation of the angiotensin-converting enzyme 2 (ACE2)42. In vitro tests have revealed its ability to reduce the number of viral copies of SARS-CoV-243 effectively.
Considering the low costs of CQ, good safety profile, in vitro activity against other viruses44,45, pre-existing supply chain with potential for increased public and private production, and knowledge about specificity and management of accumulated side effects of use in malaria, some countries have recommended the use of CQ in the treatment of COVID-19. In China, CQ was added to the COVID-19 guideline for prevention, control, diagnosis, and management on February 18, 202046. In the U.S., the Food and Drug Administration issued an emergency use authorization for CQ/HCQ to treat this disease on March 28, 202047. The European Drug Agency claimed that the two drugs should be used in clinical trials or national drug programs of emergency use for the treatment of COVID-19 on April 1, 202048.
Clinical trials are underway in several countries to evaluate the use of chloroquine or hydroxychloroquine for COVID-19. The best available evidence, until April 2020, failed to demonstrate or exclude a beneficial effect of CQ or HCQ on human coronavirus infections or viral negative by RT-PCR13-19,22. Furthermore, the results presented are limited and should be interpreted with caution since the essential outcomes for patients (e.g., mortality, rate of progression of the severe acute respiratory syndrome, and need for mechanical ventilation) were not reported in most publications.
Patients have been receiving off-label and compassionate therapies37, and the association of lopinavir and ritonavir stood out among the treatments tested for COVID-1949. These drugs are used in combination to increase plasma half-life by inhibiting cytochrome P45024. Some have raised the hypothesis that lopinavir/ritonavir inhibits protease in a similar way to SARS and MERS 3-chymotrypsin and appears to be associated with better clinical outcomes in patients with SARS50. This inhibitor, which was used mainly for HIV infection, has activity in vitro against SARS-CoV51 and appears to have some activity against MERS-CoV in animal studies52. Evidence for the use of lopinavir/ritonavir is still limited for SARS-CoV-2, and further studies should be conducted to determine the efficacy and safety of these drugs49.
The use of corticosteroids for viral pneumonia still has inconclusive effects among studies, and so far, it is difficult to have a position on the use of corticosteroids in patients with SARS-CoV-226. A diagnosis and treatment regimen was published by the National Health Commission of China, where corticosteroid therapy was indicated as adjuvant therapy, as its use was associated with a delayed viral clearance53. A meta-analysis identified that patients with severe conditions were more likely to require corticosteroid therapy and to have a higher mortality rate and adverse effects54. According to the Centers for Disease Control and Prevention (CDC)55, the use of corticosteroids cannot be indicated based on observational data. Both the CDC and the WHO believe that the use of corticosteroids should only be indicated when there is septic shock, asthma exacerbation, or chronic obstructive pulmonary disease55,56. Thus, the use of corticosteroids remains controversial57.
In total, 202 studies investigating different alternatives for the treatment of COVID-19 (Supplementary Table 8) are in progress. Most of them are being developed in China, are not yet recruiting participants, are expected to end in 2020, and are available on the ClinicalTrials.gov and Chinese Clinical Trial Registry platforms. Ongoing trials vary in the study’s design, the severity of the disease in the target population, the dosage, and the duration of treatment. The WHO58 published guidelines on the ethics of testing amid outbreaks in 2016 and is working to standardize the design of the studies.
The number of studies conducted in parallel suggests that the scientific community is making a great effort to search for safe and effective treatments. However, there is a high likelihood that we are dealing with a virtually untreatable disease, only in need of supportive measures59. Besides the financial resources involved with unproven therapies, the focus on effective interventions to prevent mortality and other important outcomes for the patient, such as social isolation, advancing testing capacity, and preventive measures, can be reduced in the general population.
A search in different databases and repositories of prepress papers and an evaluation of the methodological quality of the included studies were performed to identify studies on the theme. However, the evidence found has critical methodological weaknesses, such as a limited number of participants and a lack of control or conventional group17,21. In one of the studies, the two arms of the study received HCQ (high-dose and low-dose), which did not allow to evaluate the effect of HCQ in comparison with placebo or standard treatment15. Other limitations are the heterogeneity of the included studies concerning different dosages, routes, and duration of administration. Moreover, we were unable to detail the treatments described as standard in all studies.
There are some restrictions on the synthesis of evidence. In this synthesis, an assessment of the set of evidence generated was not conducted, employing The Grading of Recommendations Assessment, Development, and Evaluation (GRADE)60 approach, due to the heterogeneity between the studies, which evaluated neither exposures nor similar outcomes. This rapid review evidenced few overlaps between individual studies underlying the systematic reviews. Only nine duplications were identified in the three reviews included, which contained 48 primary studies.
Final considerations
Despite the various drug options identified, scientific evidence is still incipient and of low methodological quality. There is no proven efficacy and safety of any medication for human coronavirus infections. Thus, it is necessary to carry out randomized controlled clinical trials with adequate follow-up time and methods disclosed and subject to scientific peer review. Furthermore, dozens of clinical studies evaluating the efficacy and safety of drugs are underway worldwide. Periodic updating of this review is recommended to monitor scientific evidence as it becomes available.
Collaborators
Keitty Regina Cordeiro de Andrade, Viviane Karoline da Silva Carvalho, Cecilia Menezes Farinasso, Aurelina Aguiar de Lima, Roberta Borges Silva and Virginia Kagure Wachira participated in the planning, search, extraction, selection and evaluation of the quality of the studies, data analysis, writing and revision of the manuscript. Helaine Carneiro Capucho, Patrícia Medeiros-Souza, Tazio Vanni, Daniela Fortunato Rêgo and Camile Giaretta Sachetti participated in the critical review of the manuscript.
Funding
The study did not receive any funding.

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