All-oral direct antiviral treatment for hepatitis C chronic infection in a real-life cohort: The role of cirrhosis and comorbidities in treatment response
All-oral direct antiviral treatment for hepatitis C chronic infection in a real-life cohort: The role of cirrhosis and comorbidities in treatment response
Noelle Miotto 0 1
Leandro Cesar Mendes 0 1
Leticia Pisoni Zanaga 0 1
Maria Silvia Kroll Lazarini 0 1
Eduardo Sellan Lopes Goncales 0 1
Marcelo Nardi Pedro 0 1
Fernando Lopes Goncales 0 1
Raquel Silveira Bello Stucchi 0 1
Aline Gonzalez Vigani 0 1
0 Internal Medicine Department, Infectious Diseases Division, Faculty of Medicine, State University of Campinas , Campinas , Brazil
1 Editor: Han-Chieh Lin, Taipei Veterans General Hospital , TAIWAN
Hepatitis C virus (HCV) infection is the major cause of end-stage liver disease (LD) worldwide. The aim of this study was to assess sustained virological response (SVR) rates in a real-world cohort of patients with HCV infection treated with interferon-free direct antiviral agents (DAA).
Data Availability Statement: All relevant data are
within the paper.
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Patients and methods
All patients with genotypes 1, 2 or 3 HCV infection who started interferon-free treatment at a
university hospital from December 2015 through July 2017 were included. The primary
outcome was SVR at post-treatment week 12 by intention-to-treat (ITT) and modified ITT
Five hundred twenty seven patients were enrolled, 51.6% with cirrhosis. Most patients
received sofosbuvir + daclatasvir + ribavirin (60.7%) and sofosbuvir + simeprevir (25.6%).
Overall SVR rates were 90.5% for ITT and 96% for mITT. SVR rates were higher in
non-cirrhotic (94.2% in ITT and 96.8% in mITT) versus cirrhotic patients (87.1% in ITT and 95.2%
in mITT). In ITT and mITT assessments, SVR rates were higher in patients with Child-Pugh
A (n = 222, 88.7% and 95.7%, respectively) versus Child-Pugh B or C (n = 40, 80% and
90%, respectively); SVR rates were higher in patients with genotype 1 (n = 405, 92.1% and
98.2%), followed by genotype 2 (n = 13, 84.6% and 92.7%) and genotype 3 (n = 109, 84.4%
and 88.4%). Lower comorbidity index (p = 0.0014) and absence of cirrhosis (p = 0.0071)
were associated with SVR. Among cirrhotic patients, lower Model for End-Stage Liver
Disease (p = 0.0258), higher albumin (p = 0.0015), and higher glomerular filtration rate (p =
0.0366) were related to SVR. Twenty-two cirrhotic patients (8%) had clinical liver
decompensation during treatment. Complications of advanced LD were responsible for
discontinuation of treatment and death in 12 and 7 patients, respectively.
Treatment with all-oral DAA achieved high SVR rates, particularly in patients without
cirrhosis and few comorbidities. Advanced LD is associated to poor outcome, such as treatment
failure and death.
Hepatitis C virus (HCV) chronic infection affects 1.1% of the global population and is the
leading cause of end-stage liver disease, hepatocellular carcinoma (HCC) and liver-related
mortality in the Western world [1±3]. A sustained virologic response (SVR) after effective antiviral
treatment is associated with decreased risk in liver disease progression and its complications,
such as portal hypertension, hepatic decompensation, HCC, and liver transplantation [3±6].
Recently, treatment options for HCV infection and its efficacy have improved with the
development of direct antiviral agents (DAA).
The polymerase inhibitor sofosbuvir (SOF), associated with the second-generation protease
inhibitor (PI) simeprevir (SMV), or the NS5A inhibitor daclatasvir (DCV), with or without
ribavarin (RBV), allowed interferon(IFN)-free effective regimens, with SVR rates above 90%
in clinical trials [7±9]. However, those studies excluded or included few patients with advanced
liver disease, so real-life studies comprising this population are needed. Furthermore, clinical
trials also demonstrated variances in SVR rates between different genotypes, with lower SVR
rates amongst genotype 3 cirrhotic patients [9±11]. Our study aimed to assess SVR rates and to
identify underlying related factors in a large real-world cohort, including patients with
advanced liver disease treated with IFN-free regimens.
Materials and methods
We included adult (> 18 years) patients with HCV chronic infection that started IFN-free
DAA therapy at Clinic Hospital, State University of Campinas (UNICAMP), Brazil, from
December 2015 through July 2017. HCV genotypes 1, 2, and 3 were included. Chronic HCV
infection was defined as the presence of HCV antibody (Abott AxSYM Anti-HCV 3.0; Abbott
Laboratories, Wiesbaden, Germany) and detectable serum HCV RNA (Cobas Ampli Prep Taq
Man; Roche Diagnostics Systems Inc., Almere, The Netherlands). Treatment-naive patients
and those who previously failed to PEG-IFN and RBV or to PEG-IFN and RBV plus first
generation PI were included. We excluded patients with HIV infection, post-liver transplant, and
those who previously received SOF, DCV or SMV.
Stage of hepatic fibrosis evaluation
Stage of hepatic fibrosis was defined according to Metavir scoring system, transient hepatic
elastography (Fibroscan1, Echosense, Paris, France) or upon the combination of clinical and
laboratorial parameters [
]. For analysis purposes, the diagnosis of none or minimal fibrosis
was made upon histological examination (F0 or F1 stage) or liver stiffness (LS) under 7.1 kPa;
portal fibrosis was defined as Metavir F2 or LS between 7.1 and 9.5 kPa: bridging fibrosis
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comprised histological stage F3 or LS between 9.5 and 12.5 kPa. The diagnosis of cirrhosis was
made upon histological examination (F4 stage) or LS 12.5 kPa and / or the presence of
esophageal varices, ascites, and splenomegaly [12±14].
Treatment management and data collection
A questionnaire that included demographics, clinical characteristics and data about HCV
infection was completed for each patient after medical appointment. The severity of medical
conditions was estimated using Carlson's comorbidity index (CCI) [
]. The estimation of
glomerular filtration rate (eGFR) was performed using Modified Diet For Renal Disease [
Chronic kidney disease was classified according to the Kidney Disease Outcomes Quality
Initiative criteria [
]. Clinical evaluation and laboratory tests were performed at baseline and
every 4 weeks during treatment or more frequently, if needed. Serum biochemical and
haematological analysis included haemoglobin (Hb), platelets, bilirubin, albumin, creatinine,
aminotransferases, alaninotransferases, amylase, lipase, and prothrombin time. HCVRNA was
performed at baseline, at treatment week 4, at the end of treatment (EOT) and post-treatment
week 12 (PT12). Unquantifiable HCVRNA was defined as less than the lower limit of
quantification. Among cirrhotic patients, Child-Pugh and Model for End-Stage Liver Disease (MELD)
were calculated at baseline and at the EOT [
Safety was assessed by spontaneous adverse events (AE) reporting, by clinical evaluation
and by laboratory data. Serious AE was defined as any AE that led to treatment
discontinuation, decompensation of liver disease or grade 3 or 4 laboratory abnormalities. Mild anemia
was defined as Hb 10.1±11.9 g/dL for women and Hb 10.1±12.9 g/dL for men; moderate and
severe anemia was defined as Hb 8.6±10.0 g/dL and Hb 8.5 g/dL, respectively. Early therapy
discontinuation was based on the decision of the physicians attending each patient. If
treatment was interrupted by patients' decision it was considered poor tolerability other than
Treatment dose and duration
Treatment was proposed to patients following standard practices and national guidelines at
the outpatient clinic, without influence from the study team [
]. Genotype 1 patients with
Child-Pugh B or C cirrhosis or prior non-responders to first generation PI-based treatment
received SOF (400mg daily) plus DCV (60mg daily) with or without RBV for 24 weeks; the
rest of genotype 1 patients received SOF plus DCV or SMV (150mg daily) with or without
RBV for 12 weeks. Genotype 2 patients were treated with SOF plus RBV for 12 weeks.
Genotype 3 patients received SOF plus DCV with or without RBV for 12 weeks. Ribavirin was
adjusted by weight (1000mg/day for patients <75 kg and 1250mg/day for patients 75kg)
and by glomerular filtration rate (eGFR). Changes in RBV dosages were documented, and
DAA dosage did not change during treatment.
Analysis population and endpoints
The treated population comprised all the patients that received at least 1 day of the purposed
treatment. The primary endpoint was SVR, defined as unquantifiable HCVRNA at PT12. The
primary analytic approach was an intention-to-treat (ITT) assessment. The secondary analytic
approach was a modified intention-to-treat (mITT) assessment that excluded patients with
missing virologic PT12 data due to loss to follow-up or death. Secondary endpoints comprised
identification of factors associated with achievement of SVR and safety assessment.
Virologic failure was defined as absence of SVR due to no response (lack of achievement of
unquantifiable HCVRNA during treatment), virologic breakthrough (quantifiable HCVRNA
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at EOT after an unquantifiable HCVRNA during treatment), or relapse (unquantifiable
HCVRNA at EOT but quantifiable at PT12). In ITT assessment, non-virologic treatment
failure included missing HCVRNA due to loss to follow-up or death on-or-after-treatment.
We performed statistical analysis using Epi Info™, version 188.8.131.52 (Center for disease Control
and Prevention, Atlanta, Georgia, USA) and GraphPad1(GraphPad Software, La Jolla,
California, USA). Baseline continuous data were reported as median, and categorical values as
frequencies and percentages. Univariate analyses were performed using 2- tailed Fisher's, and
analysis of variation or Mann-Whitney, as appropriate. A p<0.05 was considered statistically
significant. Variables with p<0.2 were selected for a backward logistic regression model.
Study design, protocols, patient enrolment, and data collection and storage were in accordance
with ethical considerations supported by the Helsinki Declaration . The study was
reviewed and approved by the Ethics Committee for Research of the School of Medical
We included 527 patients treated with interferon-free DAA regimens, and 487 were included
for mITT efficacy (Fig 1). Table 1 shows patients' characteristics. Among all patients, median
age was 56 years, most were male (59.8%), non-black (93.4%), and
HCV-treatment-experienced (60.9%). Thirty-six patients (6.8%) had moderate chronic kidney impairment at
Fig 1. Derivation of the analysis population. ITT = intention-to-treat; LTFU = loss to follow-up; SVR = sustained
virological response; mITT = modified intention-to-treat.
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Data presented as median and range, unless otherwise noted.
²One patient did not have evaluation of liver fibrosis and treatment was indicated because of extra hepatic manifestation.
MELD, Model for End-Stage Liver Disease; HCV, hepatitis C virus; INR, prothrombin international normalize ratio; eGFR, estimated glomerular renal function; SOF,
sofosbuvir; DCV, daclatasvir; SMV, simeprevir; RBV, ribavirin; wk, weeks
baseline, and four patients were on haemodialysis. Cirrhosis was present in 51.6% of patients,
most of them (81.6%) with compensated liver disease. Genotype 1 infection was the most
prevalent (76.8%), followed by genotypes 3 (20.7%) and 2 (2.5%).
Mean duration of treatment was 12 weeks (range 1±24). Table 1 illustrates treatment
regimens and durations for each HCV genotype. Majority of patients received a combination of
SOF + DCV + RBV (60.7%) followed by SOF + SMV (25.6%), and SOF + DCV (9.1%).
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Sustained virological response
SVR outcomes for ITT and mITT are shown in Table 2 for all patients, and broken down by
genotype, cirrhotic status, and treatment regimens. Among all patients, SVR was 90.5% for
ITT and 96% for mITT. SVR was higher in non cirrhotic patients (94.2% in ITT and 96.8% in
mITT) compared to cirrhotic patients (87.1% in ITT and 95.2% in mITT). In both ITT and
mITT assessments, SVR was higher in patients with cirrhosis Child-Pugh A (88.7% and 95.7%,
respectively) than in patients with cirrhosis Child-Pugh Child B or C (80% and 90%,
In both ITT and mITT assessments, SVR was higher in patients infected with genotype 1
(n = 405, 92.1% and 98.2%), followed by a smaller group of genotype 2 (n = 13, 84.6% and
92.7%) and slightly lower in genotype 3 (n = 109, 84.4% and 88.4%).
Concerning the assorted treatment regimens for genotype 1- infected patients, SVR rates in
ITT assessment for those treated with SOF + DCV + RBV for 12 and 24 weeks, and with SOF
+ SMV were 87.1% (176/202), 92.4% (109/118), and 94.2% (129/137), respectively. For patients
with genotype 3, SVR rates were 84.3% (75/89) for patients treated with SOF + DCV + RBV,
and 85% (17/20) for those who received SOF + DCV.
Regarding baseline characteristics among all patients in ITT assessment, lower CCI
(p = 0.0014) and absence of cirrhosis (p = 0.0071) were associated with achievement of SVR. A
sub-analysis in cirrhotic patients demonstrated that lower MELD (p = 0.0258), higher albumin
(p = 0.0015), and higher eGFR (p = 0.0366) were related with SVR (Table 3.) There was no
particular variable associated with SVR among non-cirrhotic patients. Multivariate analysis did
not demonstrate any variable independently associated with SVR.
Fifty patients on ITT assessment did not achieve SVR due to virologic (n = 18) or
non-virologic (n = 32) failure. Among virologic failures, there were 1 null-responder 2 breakthroughs,
and 15 relapses. Among non-virological failures, there were 2 patients that interrupted
treatment before achieving a non-quantifiable HCVRNA; 12 patients died (4 during treatment and
8 during follow-up period); and 18 patients lost follow-up (6 during treatment and 12 after the
EOT). Individual characteristics of the 50 patients with treatment failure are shown in Table 4.
Among virologic failures, most patients (61.1%) were infected with genotype 3, 55.5% were
HCV-previously treated, and half (n = 9) had cirrhosis. Concerning non-virologic failures,
most patients had genotype 1 infection (75%), half (n = 16) were HCV-treatment experienced,
and most were cirrhotic (59.3%).
Forty-five (8.5%) patients experienced 1 or more serious AE. Mild anemia was seen in 33.9%
(n = 179), moderate anemia in 5.5% (n = 29), and severe anemia in 1.7% (n = 9) of patients.
Twenty-two cirrhotic patients (8%) had clinical liver decompensation during treatment.
Fifteen (2.8%) patients interrupted treatment due to AE: 12 due to liver decompensation, 2
due to sepsis and 1 due to severe anemia. Seven patients interrupted treatment because of
nonAE causes: 4 because of intolerance; 1 due to dysphagia caused by ischemic stroke; 1 due to
hepatocellular carcinoma -related liver transplant, and 1 for misunderstanding of correct
medication dosage. There were 12 on-and-off-treatment deaths: 2 due to ischemic stroke
(considered possibly related to treatment), 3 of sepsis, and 7 caused by complication of advanced liver
disease (all with decompensated cirrhosis and 1 also with variceal bleeding). All death were
classified as non-virologic treatment failure.
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Our cohort comprised patients infected with diverse HCV genotypes and a high proportion of
cirrhotic patients, including decompensated cirrhosis. We demonstrated high SVR rates in
ITT assessment (90.5%), and even better in mITT (96%). SVR rates were higher among
patients infected with genotype 1 and without cirrhosis. Among virologic failures, most
patients had genotype 3 HCV-infection (63.6%) and half of them were cirrhotic.
Considering genotype 1-infected patients, SVR rates in our study (92.1% in ITT and 98.2%
in mITT) were high and similar to those found in phase II Cosmos (92%), phase III
OPTMIST-1 (97%), and phase III AI44040 (98%) clinical trials, even considering that those studies
did not include or had few cirrhotic patients [7±9]. Our study had superior efficacy endpoint
among patients that received SMV-based treatments (94.2% without RBV and 90.1% with
RBV) compared to the TARGET cohort (84.2%) [
]. Moreover, we found that cirrhotic
genotype 1 patients had lower SVR rate (89.9%) compared to non-cirrhotic patients (94.6%), which
was also demonstrated by the HEPATHER study (87% and 98%, respectively) [
]. Our study
included few patients with genotype 2 infection, consequently, we were not able to perform
particular sub-analysis in this population. However, SVR rates (84.6% in ITT and 92.7% in
mITT) among those patients were similar to another Brazilian cohort (88%) [
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In our study, patients infected with genotype 3 had lower SVR rate compared to patients
with genotypes 1 and 2. Efficacy outcome by ITT assessment for genotype 3 (84.4%) was
slightly lower compared to the phase III studies ALLY-3 (89%) and ALLY-3+ (90%) [
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1 55 M 1a SOF + DCwVk+ RBV 24
2 69 M 1 SOF + DCwVk+ RBV 24
3 56 F 1b SOF + SMV 12 wk
4 41 M 1b SOF + SMV 12 wk
5 79 F 1a SOF + SMV 12 wk
6 55 M 1b SOF + SMV 12 wk
7 63 M 2 SOF + RBV 12 wk
8 58 F 3 SOF + DCwVk+ RBV 12
9 61 F 3 SOF + DCwVk+ RBV 12
10 46 M 3 SOF + DCwVk+ RBV 12
11 52 M 3 SOF + DCwVk+ RBV 12
12 56 M 3 SOF + DCwVk+ RBV 12
13 57 M 3 SOF + DCwVk+ RBV 12
14 61 F 3 SOF + DCV 12 wk
15 36 F 3 SOF + DCwVk+ RBV 12
16 52 M 3 SOF + DCwVk+ RBV 12
17 52 M 3 SOF + DCwVk+ RBV 12
18 61 M 3 SOF + DCV 12 wk
19 54 M 1a SOF + DCwVk+ RBV 24
20 76 F 1b SOF + DCwVk+ RBV 12
21 44 M 1b SOF + DCwVk+ RBV 12
22 76 M 1a SOF + DCwVk+ RBV 24
23 45 M 1a SOF + DCwVk+ RBV 12
24 55 M 1a SOF + DCwVk+ RBV 24
25 60 M 1b SOF + DCwVk+ RBV 12
26 64 F 1 SOF + DCwVk+ RBV 24
27 76 F 1b SOF + DCwVk+ RBV 12
28 55 M 1a SOF + DCwVk+ RBV 12
This could be explained due to the low proportion of cirrhotic patients in the ALLY-3 (19.8%)
compared to our study (62.4%). ALLY-3+ did not include decompensated cirrhosis and half of
the patients received treatment for 16 weeks; while 15% of our cirrhotic patients had
decompensated liver disease, and due to national guidelines, treatment duration was restricted to 12
]. Among our findings, SVR in patients with genotype 3 and cirrhosis (79.4% in
ITT and 85.7% in mITT) was somewhat lower than found among patients treated with SOF +
DCV ± RBV the cirrhotic Spanish cohort (90.6 to100%), but comparable to the European
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compassionate study with 24 weeks duration treatment (88%), and to a Brazilian cohort (85%)
[25±27]. We believe that genotype 3-infected patients, specially those with cirrhosis, are a
difficult-to-treat populations that could benefit from treatment enlargement, as demonstrated in
previous studies [26±27].
Prior studies revealed that HCV-treatment experienced patients achieved lower SVR rates
]. Strikingly, in our study patients with prior HCV treatment had greater SVR rates
(91.9% in ITT and 96.4% in mITT) compared to HCV-treatment naïve patients (88.4 in ITT
and 95.3% in mITT). This was also demonstrated by the HEPATHER cohort, even for separate
analysis between patients prior-null responders from prior relapsers and virologic
breakthroughs. These results could be justified by different history of care and selection profiles, or
even by compliance between treatment-experienced and treatment-naïve patients .
Besides cirrhosis status, we found that lower CCI index was associated with SVR
(p = 0.0014). An Egyptian cohort showed that comorbidities were more frequent in patients
with treatment failure (74.6%, p = 0.18), although CCI index was not performed [
CCI index may be an important approach for individual patients before treatment. Higher
CCI index is suitable with patients that need more attention while on-and- after treatment,
due to the risk of drug-interactions and also treatment interruption [30±31].
Among cirrhotic patients, we demonstrated that higher albumin, lower MELD score and
higher eGFR at baseline were associated with SVR achievement. Marcelin et al also showed
that lower albumin was associated with treatment failure among patients with advanced
fibrosis, and the TARGET cohort revealed that higher baseline albumin level was associated with
SVR [23±28]. Although Child-Pugh A patients had superior SVR rate (88.7%) compared to
Child-Pugh B and C (80%), Child-Pugh score was not an individual predictor of SVR
achievement. Other previous studies also demonstrated that compensated cirrhotic patients had
higher SVR rates compared to patients with decompensated liver disease, yet it was not
statistically significant, except for one cohort that evaluated SVR among elderly patients [
Nevertheless, in our study lower MELD was independently associated with treatment
response. Lastly, we found that higher eGFR was associated with SVR, which was not
demonstrated by previous real-life studies[
]. Indeed, eGFR might be a confounded variable
since it is included in MELD score. Although, higher eGFR could be associated with patients
with a better health-status, explaining its association with SVR achievement. In despite of that,
all the 4 patients with end-stage kidney disease included in our study achieved SVR12.
Our results showed that a small proportion of cirrhotic patients (8%) developed liver
decompensation while on treatment. A British cohort including a large number
decompensated cirrhotic patients (n = 409) demonstrated that 23% of those had worsening in MELD
scores of 2 points or more [
]. Maan et al followed 433 cirrhotic patients treated with DAA
and revealed that 11.5% of those experienced clinical liver decompensation, compared to 8%
of cirrhotic patients in our study [
]. Decompensation of acute-on-chronic liver disease was
also the main cause of treatment interruption due to AE (80%, n/N = 12/15) and death
onand-after treatment (58.3%, n/N = 7/12) in our casuistry. These data brings the attention to
liver decompensation during treatment as an important cause of poor outcome.
Due to the observational nature of our study, no conclusion regarding superiority of one
treatment regimen over another could be made. Also, genotype 1-infected patients with
decompensated cirrhosis and those who previously failed from first-generation protease
inhibitor received 24 weeks of DCV based-treatment, so groups that received 12 or 24 weeks of SOF
+ DCV ± RBV were not comparable. That said, no assessment between treatment duration
could be done. Another important limitation of our study is that we do not have virologic
analysis of failures. As most virologic failures were relapses rather than virologic breakthroughs
and null-responders, we expect that treatment failures would be predominantly associated
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with resistance-associated variants [
]. Additional limitations of our study is missing data
regarding Child-Pugh and MELD scores at EOT and the potential of under reporting of AE.
However, it is unlikely that serious AE, which are clinically most relevant, were missed.
In conclusion, SVR rates amongst genotype 1 patients were high and similar to clinical trails
and real-life cohorts, while SVR rates among genotype 3 patients were lower than those
studies. Lower CCI index and absence of cirrhosis were associated with SVR achievement. Among
cirrhotic patients, higher albumin, lower MELD and higher eGFR were related to treatment
response. Nevertheless a small proportion of patients had liver decompensation, it was
associated with poor outcome such as treatment interruption and death.
The authors would like to thank Dr Cecilia Amelia Fazzo Escanhoela for the histological
analyses of the liver biopsies.
Conceptualization: Noelle Miotto, Leandro Cesar Mendes, Leticia Pisoni Zanaga, Maria Silvia
Kroll Lazarini, Eduardo Sellan Lopes Goncales, Fernando Lopes Goncales, Jr, Raquel
Silveira Bello Stucchi, Aline Gonzalez Vigani.
Data curation: Noelle Miotto, Leandro Cesar Mendes, Leticia Pisoni Zanaga, Maria Silvia
Kroll Lazarini, Eduardo Sellan Lopes Goncales, Marcelo Nardi Pedro, Raquel Silveira Bello
Stucchi, Aline Gonzalez Vigani.
Formal analysis: Noelle Miotto, Aline Gonzalez Vigani.
Investigation: Noelle Miotto, Leandro Cesar Mendes, Leticia Pisoni Zanaga, Maria Silvia
Kroll Lazarini, Eduardo Sellan Lopes Goncales, Aline Gonzalez Vigani.
Methodology: Noelle Miotto, Aline Gonzalez Vigani.
Project administration: Noelle Miotto, Leticia Pisoni Zanaga, Maria Silvia Kroll Lazarini,
Raquel Silveira Bello Stucchi, Aline Gonzalez Vigani.
Resources: Noelle Miotto, Fernando Lopes Goncales, Jr, Raquel Silveira Bello Stucchi, Aline
Software: Noelle Miotto.
Supervision: Noelle Miotto, Raquel Silveira Bello Stucchi, Aline Gonzalez Vigani.
Validation: Noelle Miotto, Leticia Pisoni Zanaga, Raquel Silveira Bello Stucchi, Aline
Visualization: Noelle Miotto, Leandro Cesar Mendes, Leticia Pisoni Zanaga, Raquel Silveira
Bello Stucchi, Aline Gonzalez Vigani.
Writing ± original draft: Noelle Miotto.
Writing ± review & editing: Noelle Miotto, Leandro Cesar Mendes, Raquel Silveira Bello
Stucchi, Aline Gonzalez Vigani.
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