No difference in effectiveness of treatment simplification to boosted or unboosted atazanavir plus lamivudine in virologically suppressed in HIV-1-infected patients
No difference in effectiveness of treatment simplification to boosted or unboosted atazanavir plus lamivudine in virologically suppressed in HIV-1-infected patients
Alicia Gutierrez-ValenciaID (AGV 1 2
Coral GarcÂõa 0 1
Pompeyo Viciana 1 2
Yusnelkis MilaneÂ s- Guisado 1 2
Tamara Fernandez-Magdaleno 1 2
Nuria Espinosa 1 2
Juan Pasquau 0 1
Luis Fernando LoÂ pez-CorteÂ s (LFLC 1 2
0 Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen de las Nieves , Granada , Spain
1 Editor: Richard John Lessells, University of KwaZulu-Natal , SOUTH AFRICA
2 Unidad ClÂõnica de Enfermedades Infecciosas, MicrobiologÂõa y Medicina Preventiva, Instituto de Biomedicina de Sevilla/Hospital Universitario Virgen del RocÂõo/CSIC/Universidad de Sevilla , Sevilla , Spain
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: L.F. Lopez-Cortes, P. Viciana,
N. Espinosa and J. Pasquau have received
unrestricted research funding, consultancy fees,
and lecture fees from and have served on the
Ambispective observational study in patients with undetectable HIV-RNA who were
switched to ATVrtv or ATV400 plus lamivudine once daily. Previous virological failures (VF)
were allowed if the resistance tests showed major resistance mutation neither to ATV nor to
lamivudine. VF was defined as two consecutive plasma HIV-RNA >200 copies/mL.
Effectiveness was assessed by intention-to-treat and on-treatment analyses. Plasma and
intracellular ATV Ctrough were measured by LC-MS/MS.
A total of 246 patients were included. At week 48, the Kaplan±Meier estimation of efficacy
within the ATVrtv and ATV400 groups were 85.9% [95% confidence interval, (CI95), 80.3±
91.4%] versus 87.6% (CI95, 80.1±94.1%) by intention-to-treat analysis (p = 0.684), and
97.7% (CI95, 95.2±100%) versus 98.8% (CI95, 97.0±100%) by on-treatment analysis (p =
0.546), respectively. Plasma and intracellular Ctrough were significantly higher with ATVrtv
than with ATV400 (geometric mean (GM), 318.3 vs. 605.9 ng/mL; p = 0.013) and (811.3 vs.
advisory boards of Abbott, Bristol-Myers Squibb,
Gilead Sciences, Janssen-Cilag, Merck Sharp &
Dohme, and ViiV Healthcare. The other authors
have no conflicts of interest to disclose. This does
not alter our adherence to PLOS ONE policies on
sharing data and materials.
2659.2 ng/mL; p = 0.001), respectively. Only 14 patients had plasma Ctrough below the
suggested effective concentration for ATV (150 ng/mL). No relationship between plasma or
intracellular Ctrough and VF or blips were found.
Boosted or unboosted ATV plus lamivudine is effective and safe, and the lower plasma
Ctrough observed with ATV400 do not compromise the effectiveness of these simplification
regimens in long-term virologically suppressed HIV-1-infected patients.
The first attempts of simplifying antiretroviral treatment (ART) in virologically suppressed
HIV-1-infected patients were less effective compared with maintaining triple-drug therapy,
probably due to the low genetic barrier and/or antiviral potency of the drugs used at that time
]. In recent years, the availability of new drugs with improved genetic barrier and potency,
particularly ritonavir-boosted protease inhibitors (PI), have led to a re-emergence of
simplification strategies. The key rationales for simplifying ART are the reduction of both
druginduced toxicities and the risk of resistance mutations in case of virological failure, as well as
the cost [3±7]. Two randomized clinical trials have demonstrated non-inferiority of ATVrtv
plus lamivudine (3TC) compared with ATVrtv plus two nucleos(t)ide reverse transcriptase
inhibitors (NRTIs) in HIV-infected patients with virological suppression (VL) [8±10]. Based
in their results, dual therapy including atazanavir 300 mg plus ritonavir 100 mg (ATVrtv) plus
3TC might represents a good simplification strategy, as ATV has been associated with lower
rates of lipid abnormalities than other PIs [11±13] and has a good resistance profile. However,
ATVrtv is not always well tolerated due to potential toxicity related both to high ATV plasma
concentrations as well as to the use of ritonavir, including gastrointestinal disturbances, lipid
profile alterations, and hyperbilirubinemia. Indeed, it has been observed that switching
patients with virological suppression on ATVrtv plus two NRTIs to 400 mg unboosted ATV
once daily (ATV400) improves toxicity and tolerability without loss of virological suppression
However, dual therapy comprising ATV400 plus 3TC has been rarely explored, although
some data suggest similar effectiveness as compared to ATVrtv plus 3TC in patients on
longlasting virological suppression [
A minimum plasma trough concentration (concentration at the end of interval dosing;
Ctrough) of 150 ng/mL has been proposed for ATV to be effective when given with two NRTIs
]. Since the pharmacokinetic variability of ritonavir-boosted ATV is high, it is not
uncommon for patients to show an ATV plasma trough concentration (Ctrough) below this
recommended level. In the case of ATV400, the plasma concentrations are lower and show an even
higher variability than with ATVrtv [22±24]; however, it remains unknown whether this
influences the effectiveness of the drug to a higher extent than with ATVrtv when administered in
Therefore, the aim of this study was to determine the effectiveness of boosted and
unboosted ATV plus 3TC in virologically suppressed HIV-1-infected patients, as well as to
evaluate the relationship between plasma and intracellular ATV Ctrough with the virological
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Material and methods
This ambispective observational study was carried out at two Spanish University Hospitals. All
patients with virological suppression at least for one year who switched to a dual therapy with
either ATVrtv or ATV400 plus 3TC once daily from January of 2011 to May of 2014 (retrospective
part) and from June 2014 to December 2015 (prospective part) were included. The reasons for
switching were the presence of adverse effects (AEs) with previous regimens, drug-drug
interactions and simplification to a regimen with a lower pill burden. These regimens were not
prescribed in case of pregnancy, hepatitis B coinfection or concomitant use of drugs with potential
interactions with ATV pharmacokinetics. Additionally, the presence of cirrhosis with clinical or
analytical data of liver failure, and 1 major resistance mutations to ATV (I50L, I84V, and N88S)
or 3TC (K65R/E/N or M184I/V) in the genotypic resistance tests lead to exclusion of the patient.
The study was designed and conducted according to the principles of the Declaration of Helsinki
and was approved by the Spanish Agency of Medicines and Healthcare Products and the
Coordinating Committee on Ethics in Biomedical Research of AndalucÂõa. All patients provided signed
informed consent, except in those retrospective cases as, according to Spanish law, the
retrospective studies do not require informed consent if only completely anonymous information from
existing records was collected, thereby ensuring the protection of personal data in accordance
with the Personal Data Protection Organic Law15/199 enacted on December 13, 1999.
Endpoints, follow-ups, and assessments
The primary clinical endpoint was treatment effectiveness, measured as the percentage of patients
who maintained virological suppression after 48 weeks according to intention-to-treat analysis
(non-complete/missing = failure). VF was defined as a confirmed plasma HIV-RNA of >200
copies/mL, considering the time of the first assessment meeting the failure criteria as the time of failure,
or a single HIV-RNA level >200 copies/mL in case of subsequent loss of follow-up. A cut-off level
of 200 copies/mL was chosen since it represents a more accurate measurement of VF than lower
cut-off values [
]. The change of ATVrtv to ATV400 due to intolerance to ritonavir was not
considered as failure. Viral blip was defined as a single HIV-RNA value >50 copies/mL without
subsequent confirmation. As a secondary outcome, virological efficacy and its relationship with plasma
and intracellular ATV concentrations were assessed in an on-treatment approach where patients
who were lost to follow-up, voluntarily dropped, discontinued therapy due to AEs or changed the
study regimen due medical decision without VF criteria were excluded from analyses.
A standard checklist was used for recording information extracted from electronic medical
records, including demographic variables, clinical and laboratory data at baseline, after 1
month, and every 3 months thereafter. CD4+ T cell counts and plasma HIV-RNA were
measured by flow cytometry and the Cobas AmpliPrep-Cobas TaqMan HIV-1 test (v 2.0. Roche
Diagnostics, Basel, Switzerland; lower detection limit of 20 copies/mL), respectively. AEs were
categorized via the standardized toxicity-grade scale used by the AIDS Clinical Trials Group
]. However, in patients with chronic hepatitis C or cirrhosis, toxicity was classified
according to changes relative to the baseline values rather than the upper limit of normality: grade 0,
<1.25 x baseline; grade 1, (1.25 to 2.5) x baseline; grade 2, (2.6 to 3.5) x baseline; grade 3, (3.6
to 5) x baseline; and grade 4, >5 x baseline.
A pharmacokinetic study was performed in the subgroup of patients included prospectively,
where at least one sample per patient was obtained during the follow-up. Blood samples for
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ATV Ctrough were collected into EDTA and cell preparation tubes (CPTs; Becton Dickinson
Vacutainer) at 24 ± 0.5 h after the previous dose taken after a standard breakfast (otherwise,
blood samples were discarded). Within 1 h after collection, the tubes were centrifuged at 1500
g for 20 min at room temperature. Plasma was transferred to cryotubes and stored at -80Ê C
until analysis. The cell layer from the CPT tubes was transferred to 15 mL Falcon tubes,
peripheral blood mononuclear cells (PBMC) were then fast washed twice in 10 mL ice-cold
0.9% NaCl solution and centrifuged at 1500 g for 10 min at 4ÊC. The cell pellets were
transferred to Eppendorf tubes and washed with 1.5 mL ice-cold 0.9% NaCl solution. Once
centrifuged, the supernatants were aspirated and the cell pellets were weighed. Afterwards, the
pellets were dissolved in 1ml extraction solution (methanol:water, 70:30, v/v), and then stored
at -80ÊC, for no longer than 3 months, until analyses. For ATV intracellular concentrations,
PBMC aliquots were weighed and their volume was calculated as volume = weight/density.
Since the density of mononuclear cells is 1.077 and that of plasma 1.030, the weight of the
aliquots was equalized with their volume.
Plasma and intracellular concentrations were determined by LC-MS/MS. The separation
was performed on a Phenomenex Luna C18 (5 μm, 150 x 2.0 mm) analytical column. The
mobile phase was composed of a 2 mM ammonium acetate 0.1% formic acid and acetonitrile
0.1% formic acid. The drugs were extracted from the blood plasma by protein precipitation,
using acetonitrile containing a deuterated internal standard. The standard curves were highly
linear over the range of 10 to 2000 ng/mL. The intra- and inter-assay precision and accuracy
were <15% in both biological samples.
Categorical variables were compared using the χ2 test or the FisherÂs exact test, while
quantitative variables were analyzed using the StudentÂs t test or the Mann±Whitney nonparametric
test, respectively, according to their distribution. The ATV Ctrough were summarized as
geometric means (GM), interquartile range (IQR), and range. The intra- and inter-subject
variability in ATV Ctrough was assessed by the coefficients of variation (CV) of all the available
values from each patient throughout the follow-up period. The correlations between plasma
and intracellular concentrations were assessed by Spearman's correlation coefficients.
Timeto-event analyses were performed by using Kaplan±Meier survival curves and the log rank test.
Variables with p-values < 0.2 in the univariate analysis, as well as those that potentially affect
the efficacy of the treatments, such as age and gender, were entered into Cox proportional
hazard models. The adjusted hazard ratio (AHR) and the respective 95% confidence intervals (CI)
were calculated. Statistical analyses were performed using the IBM software (SPSS v. 23.0,
Chicago, USA), and p-values <0.05 were considered significant.
A total of 246 patients were included in the study, 149 on ATVrtv and 97 on ATV400, whose
baseline characteristics are summarized in Table 1. Eighty-two and seventy-eight patients were
included prospectively in the ATVrtv and ATV400 group, respectively. Baseline characteristics
of the patients according to the time of inclusion are provided in S1 Table.
The reasons for switching to dual therapy based on ATV were AEs with previous regimens
(38.6%), drug-drug interactions (12.2%), and simplification (49.2%). Before switching to dual
therapy, 69.5% of the patients were on an ATVrtv-based regimen. Sixty-one patients (25%) had
experienced a previous VF while on PI-based regimens (saquinavir, 36.1%; indinavir, 32.7%;
nelfinavir, 16.4%; lopinavir, 11.5% and fosamprenavir, 3.3%), but no major resistance
mutations for ATV were found in the genotype resistance tests just after these VFs. Eighty-eight
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ATVrtv + 3TC n = 149
ATV400 + 3TC n = 97
percent of these patients had a subsequent treatment based on ritonavir-boosted PI. During
the follow-up, none of the patients changed from ATVrtv to ATV400.
Effectiveness and safety
After a follow-up of 48 weeks, the Kaplan±Meier estimates of effectiveness by
intention-totreat analysis were 85.9% (CI95, 80.3±91.4%) and 87.6% (CI95, 81.0±94.1%), (p = 0.684) for
ATVrtv and ATV400 plus 3TC, respectively. The corresponding values obtained by
on-treatment analyses were 97.7% (CI95, 95.2−100%) and 98.8% (CI95, 97.0−100%) (p = 0.546). When
comparing the effectiveness in retrospectively and prospectively included patients, no
differences were found (data not shown). Overall, three cases of VF occurred in the ATVrtv group
(at month 3, 9 and 12) and only one case (at month 6) in the ATV400 group; no results for
genotype tests were available due to low HIV-RNA levels that impeded amplification. Two of
these patients achieved virological suppression three months later; one of them by switching to
a triple therapy regimen, and another one while continuing with the ATV dual therapy after
adherence counseling. Treatment effectiveness was not affected by sex, presence of chronic
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AHR (95% CI)
AHR: adjusted hazard ratio; CI: confidence interval; VF: virological failure; PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; INSTI, integrase
strand transfer inhibitor; ATVrtv: ritonavir-boosted atazanavir; ATV400: unboosted atazanavir
entered as continuous variable in the multivariate analysis; Virological success: proportion of patients with plasma HIV-RNA < 20 copies/mL at 48 weeks.
hepatitis C, cirrhosis, previous ART, blips, previous VF or treatment group. In univariate
analysis, only HIV risk factor was associated to high rate of treatment failure. This factor remained
significant when a multivariate analysis was performed (Table 2).
In addition to VF, other treatment failures in the ATVrtv group were due to AEs [grade 3
hyperbilirubinemia (n = 2; 1.3%)], loss to follow-up or voluntary treatment drop-out [n = 9
(6.0%)], and change of treatment to a single-tablet regimen due to medical decision without
underlying VF criteria or AEs [n = 7 (4.7%)]. In the group of ATV400 the numbers of
non-virological failures were 1 (1%) for AEs (grade 1 gastrointestinal disorder), 6 (6.2%) for loss to
follow-up, and 4 (4.1%) for change of treatment by medical decision. All patients had an
undetectable viral load at the time of the last available HIV-RNA assessment on ATV.
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During the 48 weeks of follow-up, 20 (13.4%) patients on ATVrtv experienced blip episodes
(1 blip, 17 patients; 2 blips, 3 patients), while only eight (8.2%) patients on ATV400 experienced
nine blip episodes (p = 0.148), with a median HIV-RNA of 129 copies/mL (IQR, 79±273).
The median increase in CD4+ T cell counts from baseline to week 48 was 20 cells/μL (IQR,
-80−124) and 50 cells/μL (IQR, -85±133) in the ATVrtv and ATV400 groups, respectively, being
inversely proportional to the baseline CD4+ T cell counts (r = -0.248 and -0.375, respectively;
p = 0.006)
Aminotransferase level elevations throughout the follow-up period occurred in 4 patients
in the ATVrtv group (grade 1, 2; grade 2, 2), three of them suffered chronic hepatitis C, and in
1 patient in the ATV400 group (grade 1), who was also coinfected by hepatitis C virus. These
alterations were transient and improved without treatment modification in all cases.
Regarding changes in lipid profiles between baseline and week 48, no significant differences between
the ATVrtv and ATV400 groups were observed, with median changes (mg/dL) of 8 (IQR, -10±
28) versus -12 (IQR, -39±22) in fasting total cholesterol, 1 (IQR, -7±7) versus -2 (IQR, -11±1)
in HDL-cholesterol, 12 (IQR, -10±34) versus -12 (IQR, -27±9) in LDL-cholesterol, and 4 (IQR,
- 45±52) versus -25 (IQR, -62± -1) in triglycerides, respectively.
Pharmacokinetics of ATV
The pharmacokinetics study was conducted in a sub-group of 63 and 78 patients in the ATVrtv
and ATV400 group, respectively. ATV Ctrough were determined in 339 plasma samples (ATVrtv,
108; ATV400, 231), and in 35 PBMCs samples of each group (Fig 1). In both plasma and
intracellular compartments, the ATV Ctrough were higher with ATVrtv than with ATV400. In plasma
samples, the ATV concentrations ranged from 49.6 to 3698.0 ng/mL with a GM of 605.9 ng/
mL (IQR, 370.4±1063.3) for ATVrtv and from 45.1 to 1755.0 ng/mL (GM, 318.3 ng/mL; IQR,
218.5±483.4) for ATV400 (p <0.001). Whereas in PBMCs samples, the corresponding values
were 2659.2 (IQR, 1213.3±5940.7; range 163.7±10743.0) vs. 811.3 ng/mL (IQR497.5±1180.4;
range 235.8±8778.6) (p <0.001) for ATVrtv and ATV400, respectively. Likewise, the mean
intracellular penetration, evaluated as intracellular/plasma Ctrough ratios was higher in the ATVrtv
group than in the ATV400 group (4.39 vs. 2.54; p <0.001). There was a correlation between the
plasma and intracellular Ctrough in patients taking ritonavir-boosted ATV (r = 0.754, p <
0.001), but not in those on unboosted ATV (r = 0.252, p = 0.123).
ATV concentrations below the suggested minimum effective concentration of 150 ng/mL
were detected in two (1.8%) samples from 2 patients of the ATVrtv group and 43 (17.7%)
samples from 12 patients of the ATV400 group. Given the low number of VF, it was not possible to
establish any relationship between VF and plasma or intracellular concentrations, however,
none of the patients with plasma ATV Ctrough below 150 ng/mL had VF. No association
between blip episodes and a low ATV Ctrough was observed. Likewise, there were no relationships
Fig 1. Atazanavir trough concentrations (Ctrough) in plasma (A), intracellular (B), and intracellular/plasma ratios (Ic/
P) in patients receiving once-daily ritonavir-boosted atazanavir (300/100 mg) (ATVrtv) or unboosted atazanavir (400
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between plasma and intracellular ATV concentrations and weight or body mass index, and
there were no differences in plasma and intracellular ATV concentrations with respect to
gender or the presence of cirrhosis.
For the ATVrtv and ATV400 groups, the median intra-subject variability for ATV was 32.3%
and 44.6% in plasma samples and 34.5% and 40.3% for intracellular ATV. The corresponding
median inter-subject variability was 197.23% and 99.23% in plasma, and 118.8% and 97.2% for
In the last years, several ART simplification strategies have been studied in order to reduce the
severity or even avoid AEs from chronic drug exposure, lower the risk of HIV-1 drug
resistance, and achieve more cost-effective regimens. Among them are dual therapies based on
ritonavir-boosted PIs in combination with 3TC or other drugs that have shown good efficacy rates
and safety profiles, being this simplified regimen an option in low resource settings or when
clinicians prefer the least number of drugs possible for their patients. [11±13, 28±30]. ATV is
the only HIV-1 protease inhibitor currently in use that can be administered without a
pharmacokinetic enhancer, although a dose increase from 300 to 400 mg daily is recommended for
the unboosted regimen. Apart from the prevention of potential drug-drug interactions, this
adaptability enables to manage both ritonavir-induced toxicity and hyperbilirubinemia caused
by high ATV concentrations.
In spite of being a study performed in the routine clinical practice, a high effectiveness of
ATV plus 3TC was observed at 48 weeks, although it should be taken into account that most of
patients of the study were virologically suppressed for a long time. Furthermore, less than 2%
of the population presented AEs that led to treatment discontinuation, which may partly be
explained by the large proportion of patients who were already on an ATVrtv-based regimen
before switching to dual therapy. Our results are similar to those reported by the ATLAS-M
clinical trials [
], where the efficacy rates at week 48 by intention-to-treat and on-treatment
analyses were 89.5% (CI95, 84.3±94.7%) and 90.1% (CI95, 85.0±95.2%) respectively, and even
better than those in the SALT trial [
] that found an efficacy rates of 78% and 83%. Both trials
demonstrated the non-inferiority of this combination compared to ATVrtv + 2 plus two
NRTIs in long-term supressed patients. To our knowledge, only two studies of dual therapy
comprising ATV400 plus 3TC [19±20] are available. In one, patients with virological
suppression on ATV400 plus two NRTIs were switched to ATV400 plus 3TC or emtricitabine, without
any VF or discontinuation after 48 weeks. In the other study, treatment-experienced
HIVinfected patients were switched from triple therapy to boosted or unboosted ATV plus 3TC
with no VF. However, the latter study only analyzed the first six months after switching to dual
therapy, and sample sizes were as low as 40 and 20 patients, respectively.
In accordance with previous pharmacokinetic studies, the herein presented work finds
lower ATV Ctrough in the non-boosted regimen as compared with the ritonavir-boosted
regimen both in plasma and on intracellular level [31±33]. The underlying mechanism is likely the
potent inhibitory effect of ritonavir on P-glycoprotein, of which atazanavir is substrate, thus
facilitating a better absorption and the accumulation of the drug on the intracellular level [34±
35]. In the ATV expanded access program, Gonzalez de Requena et al. [
] found that an ATV
Ctrough lower than 150 ng/mL was associated with a high probability of VF in PI-experienced
patients, most of them showing plasma HIV-RNA loads higher than 1000 copies/mL. In
contrast, none of the patients with a plasma ATV Ctrough below 150 ng/mL had VF in the present
study, although it is to note that the clinical condition of the herein analyzed populations was
different regarding their virological and immunologic status.
8 / 12
One of the limitations of this study is that in the last years the use of ATVrtv is progressively
decreasing since it is being replaced by a co-formulation including the pharmacokinetic
enhancer cobicistat, which is not analyzed in the present study. However, two randomized,
crossover bioequivalence studies have shown that ATV/cobicistat (300/150 mg) provides
bioequivalent ATV exposures as compared to ATVrtv, both in healthy volunteers and
treatmentnaïve adults infected with HIV-1 [36±37]. Although cobicistat shows a better tolerance and
drug-drug interaction profile than ritonavir, in some settings it should be avoided and ATV400
may be a good alternative. Another limitation is the low number of blood samples for
pharmacokinetics study, since this substudy was only conducted in the prospective part. However, the
determination of ATV plama levels was not the primary aim of the study and furthermore, still
a considerably number of samples were obtained.
In conclusion, our data suggest that boosted or unboosted atazanavir plus lamivudine
represent comparable simplification strategies regarding effectiveness and safety in HIV-infected
patients with long-term virological suppression. Although lower plasma and intracellular ATV
Ctrough is observed with ATV400, this does not appear to compromise the effectiveness of these
regimens in virologically suppressed patients. However, the lasting efficacy of this regimen
would need further investigation with clinical trials.
S1 Table. Baseline characteristic according to period of inclusion and treatment group. M
(IQR), Mean (interquartile range). ATVrtv, atazanavir boosted with ritonavir. ATV400,
unboosted-atazanavir. ART, antiretroviral treatment. PIrtv, ritonavir-boosted protease
inhibitor. NRTIs, nucleoside reverse transcriptase inhibitors. INSTI, integrase strand transfer
The authors are indebted to the patients for their involvement in this study.
Conceptualization: Alicia Gutierrez-Valencia, Juan Pasquau, Luis Fernando LoÂpez-CorteÂs.
Data curation: Alicia Gutierrez-Valencia, Luis Fernando LoÂpez-CorteÂs.
Formal analysis: Alicia Gutierrez-Valencia, Luis Fernando LoÂpez-CorteÂs.
Funding acquisition: Alicia Gutierrez-Valencia, Luis Fernando LoÂpez-CorteÂs.
Investigation: Alicia Gutierrez-Valencia, Coral GarcÂõa, Pompeyo Viciana, Yusnelkis
Guisado, Tamara Fernandez-Magdaleno, Juan Pasquau, Luis Fernando LoÂpez-CorteÂs.
Methodology: Alicia Gutierrez-Valencia, Juan Pasquau, Luis Fernando LoÂpez-CorteÂs.
Resources: Nuria Espinosa.
Supervision: Alicia Gutierrez-Valencia, Luis Fernando LoÂpez-CorteÂs.
Writing ± original draft: Alicia Gutierrez-Valencia.
Writing ± review & editing: Luis Fernando LoÂpez-CorteÂs.
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