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Original article
Elimination of hepatitis C virus infection from a hemodialysis unit and impact of treatment on the control of anemia
Eliminación de la hepatitis C de una unidad de hemodiálisis e impacto del tratamiento en el control de la anemia
Francesc Maduella, Lara Belmara, Jésica Ugaldea, Montserrat Lagunob, María Martínez-Rebollarb, Raquel Ojedaa, Marta Ariasa, Lida Rodasa, Florencia Rossia, Laura-Patricia Llovetc, Leonardo Nicolás Gonzáleza, Josep Mallolasb, Maria-Carlota Londoñoc,
Corresponding author
mlondono@clinic.cat

Corresponding author.
a Department of Nephrology, Hospital Clínic Barcelona, Barcelona, Spain
b HIV/AIDS Unit, Infectious Disease Service, Hospital Clínic, University of Barcelona, Barcelona, Spain
c Liver Unit, Hospital Clínic Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
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      "es" => array:1 [
        "titulo" => "Eliminaci&#243;n de la hepatitis C de una unidad de hemodi&#225;lisis e impacto del tratamiento en el control de la anemia"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flowchart of the patients with HCV infection detected in the HD unit&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Recent data estimates that the global prevalence of hepatitis C virus &#40;HCV&#41; infection is around 1&#46;6&#37; with a viremic prevalence of 1&#46;1&#37;&#46; This corresponds to 80 million people infected with HCV worldwide&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a> Hepatitis C infection is a common cause of liver disease in patients with chronic kidney disease &#40;CKD&#41; who receive long-term renal replacement therapy and it is associated with an increased risk of death&#44; hospitalization&#44; anemia and a reduced quality of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">2&#8211;4</span></a> Dialysis Outcomes and Practice Pattern Study &#40;DOPPS&#41; showed a prevalence of HCV infection in hemodialysis &#40;HD&#41; patients of 7&#46;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> However&#44; some studies suggest that the prevalence may be underestimated due to the presence of occult HCV infection&#44; defined as the presence of HCV-RNA in hepatocytes and absence of anti-HCV antibodies in routine serological tests&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">3</span></a> The risk of infection varies according to the type of renal replacement therapy &#40;being higher in patients treated with maintenance HD&#41;&#44; the time on HD&#44; and the prevalence of HCV infection in the specific dialysis unit&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">3&#44;5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Chronic HCV infection in HD patients is associated with an increase in mortality rate not only due to liver causes&#44; but also related with cardiovascular disease&#44; anemia&#44; hepatitis B virus &#40;HBV&#41; or human immunodeficiency virus &#40;HIV&#41; coinfection&#44; and essential mixed cryoglobulinemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">3&#44;5&#8211;7</span></a> In addition&#44; HCV infection contributes to an increase morbidity and mortality after kidney transplantation&#46; Indeed&#44; hepatitis C positive kidney transplantation recipients are at increased risk of developing de novo and recurrent membranous nephropathy&#44; membranoproliferative glomerulonephritis and transplant glomerulopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Anemia is a common complication of patients with chronic kidney disease&#46; Symptoms generally occur when hemoglobin levels are below 10<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#44; but can be more severe when kidney function worsens&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a> More importantly&#44; anemia has been associated with an increased mortality and a reduced quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> There is a scarcity of information on the role of HCV and CKD-related anemia&#44; but there are some data showing that HCV positive patients have low hemoglobin levels and higher EPO dose requirements compared to uninfected patients&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> However&#44; the impact of HCV infection elimination on the control of anemia is unknown&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">New direct-acting antivirals &#40;DAAs&#41; have demonstrated their efficacy and safety on the treatment of HCV in patients with advanced CKD on HD&#44; with sustained virological response &#40;SVR&#41; rates ranging between 90&#37; and 100&#37; and excellent safety data&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">12&#8211;15</span></a> Therefore&#44; we hypothesized that HCV infection can be safely eliminated from HD units in order to avoid the risk of new HCV infections among HD patients and staff and that HCV elimination could impact on renal function and CKD-related complications&#46; The aims of the study were to determine the success in eliminating HCV infection from our dialysis unit after DAAs therapy in all patients on HD&#44; and to evaluate the impact of therapy on clinical and analytical outcomes&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design and antiviral therapy</span><p id="par0025" class="elsevierStylePara elsevierViewall">This is a prospective&#44; observational&#44; single center study&#44; in which all HCV-RNA positive patients in our HD unit &#40;at Hospital Cl&#237;nic Barcelona and its associated dialysis centers&#41; received antiviral therapy with an interferon &#40;IFN&#41;-free regimen within a 3 year period &#40;April 2014 to March 2017&#41;&#46; The antiviral regimen was decided by the treating physician based on published guidelines and information available at the time of treatment indication &#40;Asunaprevir &#91;ASV&#93;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Daclatasvir &#91;DCV&#93;&#44; Ombitasvir&#47;Paritaprevir&#47;ritonavir with or without Dasabuvir &#91;3D or 2D&#93;&#44; Grazoprevir &#91;GZR&#93;&#47;Elbasvir &#91;EBV&#93;&#44; or Sofosbuvir &#91;SOF&#93;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DCV&#41;&#46; Direct-acting antivirals were administered according to the recommendations of the specific insert packages&#46; The usage and dose of RBV were also decided by the treating physician according to the treatment regimen recommendations and the status of the patient&#46; The duration of therapy was 12 or 24 weeks according to recommendations of the European Association for the Study of the Liver &#40;EASL&#41; guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> Since the aim of the study was the elimination of HCV infection from HD unit&#44; the presence of significant comorbidities was not considered as a contraindication to receive antiviral therapy&#46; Potential drug&#8211;drug interactions were actively investigated and if detected&#44; concomitant medications were modified appropriately&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Monitoring</span><p id="par0030" class="elsevierStylePara elsevierViewall">For each patient&#44; data on age&#44; gender&#44; previous comorbidities&#44; time on dialysis&#44; duration of each dialysis session&#44; etiology of CKD&#44; HBV or HIV coinfection&#44; and previous HCV treatments were collected at baseline&#46; Liver tests &#40;aspartate aminotransferase &#91;AST&#93;&#44; alanine aminotransferase &#91;ALT&#93;&#44; gamma glutamyl-transpeptidase &#91;GGT&#93;&#44; alkaline phosphatase &#91;ALP&#93; and bilirubin&#41;&#44; inflammatory markers &#40;C-reactive protein&#44; CRP&#41; and parameters for the control of anemia &#40;hematocrit&#44; hemoglobin&#44; ferritin&#44; transferrin saturation index &#91;TSI&#93;&#44; dose of darbepoetin and intravenous iron&#41; were monitored monthly from 3 months before starting antiviral therapy to the end of the follow-up &#40;12 months after treatment discontinuation&#41;&#46; Liver stiffness measurements &#40;LSM&#41; were performed at baseline and 3 months after treatment discontinuation&#46; Both determinations were conducted after HD session to avoid the impact of fluid overload on LSM&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">HCV-RNA was measured by quantitative polymerase chain reaction with a lower limit of quantification of 15<span class="elsevierStyleMonospace">Y</span>IU&#47;L &#40;Versant kPCR Molecular Systems&#44; Siemens Medical Solutions Diagnostics&#44; New York&#44; USA&#41; at baseline and week 4 of antiviral therapy&#44; end of therapy and 12 weeks after treatment discontinuation&#46; Afterwards&#44; HCV-RNA was monitored every 3 months according to local protocol at the HD unit&#46; Sustained virological response &#40;SVR&#41; was considered when HCV-RNA was negative 12 weeks after the end of treatment&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Side effects were assessed during treatment and within 12 months of treatment discontinuation&#46; All adverse events referred by the patient were collected&#46; Special attention was given to the development or worsening of anemia &#40;defined as hemoglobin levels<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#41;&#46; The management of anemia was carried out by correcting the dose of darbepoietin and intravenous iron according to hemoglobin&#44; hematocrit&#44; ferritin&#44; and transferrin saturation index &#40;TSI&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Continuous variables are expressed as mean &#40;standard deviation&#41;&#46; Categorical variables are expressed as number and percentage&#46; Comparisons between categorical variables were performed by Chi-square test or Fischer test as appropriate&#46; Comparisons between continuous variables were performed by <span class="elsevierStyleItalic">T</span>-test or non-parametric tests&#46; A one-way repeated measures ANOVA was used to determine whether there was a statistical difference between paired analyses&#46; A <span class="elsevierStyleItalic">p</span> value &#60;0&#46;05 was considered significant&#46; Statistical analysis was performed using the statistical SPSS version 23&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Effectiveness and tolerability of antiviral therapy</span><p id="par0050" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; 26 &#40;10&#37;&#41; out of the 262 attending our HD unit during the study period were anti-HCV and HCV-RNA positive&#46; During the study period&#44; 4 patients discontinued HD treatment &#40;2 due to kidney transplantation&#44; 1 patient was transfer to another center&#44; and 1 patient died due to hepatocellular carcinoma&#41;&#44; and 2 patients did not require antiviral treatment due to spontaneous HCV-RNA negativization&#46; Thus&#44; 20 patients were candidates to receive DAAs treatment&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">The characteristics of the 20 treated patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Briefly&#44; 65&#37; were male&#44; with a mean age of 53&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;3 years&#44; infected with genotype 1b &#40;60&#37;&#41;&#44; and stable on HD over a period of 82<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>79 months&#46; Twenty percent of patients were non-responders to a previous course of an IFN-based therapy&#46; The dialysis modality was on-line hemodiafiltration with post-dilutional infusion in all patients&#46; Twenty-five percent &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; of patients had diabetes mellitus&#44; 40&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; had cirrhosis and 25&#37; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41; had other viral coinfections &#40;3 HIV infection&#44; 2 HBV infection&#41;&#46; The etiologies of CKD were&#58; glomerulonephritis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#44; 40&#37;&#41;&#44; diabetic nephropathy &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#44; 15&#37;&#41;&#44; amyloidosis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44; 10&#37;&#41;&#44; chronic interstitial nephropathy &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44; 10&#37;&#41;&#44; nephroangiosclerosis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44; 5&#37;&#41;&#44; obstructive uropathy &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44; 5&#37;&#41;&#46; In the remaining 3 patients &#40;15&#37;&#41; the etiology of CKD was unknown&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">The most commonly used DAAs regimen was Ombitasvir&#44; Paritaprevir&#47;ritonavir and Dasabuvir &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#59; 45&#37;&#41;&#46; Ribavirin &#40;RBV&#41; was added only in one patient infected with genotype 1a&#46; Interestingly&#44; 3 patients infected with genotypes 2 or 3 received a Sofosbuvir-based combination &#40;off-label&#41;&#46; The specific treatment&#44; dose and duration are shown in Supplementary Table 1&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">At week 4 of therapy&#44; viral load for HCV was undetectable in all patients and all of them achieved SVR&#46; No reinfections were observed in any of the subjects during the follow-up period&#46; After achieving SVR&#44; 3 patients who asked for it were relocated in dialysis shifts for HCV negative patients&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Medication was well tolerated with mild side effects in 40&#37; of patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; None of these side effects led to treatment discontinuation&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Impact of therapy on clinical and analytical outcomes</span><p id="par0075" class="elsevierStylePara elsevierViewall">As expected&#44; SVR was associated with an improvement in liver tests &#40;Supplementary Table 2&#41; and liver stiffness measurement determined at the time of SVR &#40;from 9&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;1<span class="elsevierStyleHsp" style=""></span>kPa to 7&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;0<span class="elsevierStyleHsp" style=""></span>kPa&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;008&#41;&#46; C-reactive protein did not change significantly changed during and after DAA therapy &#40;Supplementary Table 2&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">We observed an improved control of anemia after DAAs treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; with a significant increase hemoglobin and hematocrit levels after the end of treatment &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;017 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#59; respectively&#41;&#46; This was associated with a tendency toward a decrease in the dose of intravenous iron &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;064&#41;&#46; There were no significant changes in the dose of darbepoetin and ERI index&#46; In addition&#44; ferritin levels and transferrin saturation index did not significantly changed after treatment discontinuation &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">Here&#44; we showed for the first time that with the new DAAs treatments it is possible to eliminate HCV infection from HD units&#46; Despite the prevalence of HCV in patients on HD having declined significantly in recent years&#44; it is still higher than that of the general population carrying a significant increase in morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">19&#44;20</span></a> The international observational study on the long-term guidelines and results of patients on HD &#40;DOPPS&#41; reviewed 76&#44;689 adult patients between 1996 and 2015&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> The prevalence of HCV infection observed among countries participating in all phases of DOPPS was 14&#46;3&#37; in phase 1 &#40;1996&#8211;2001&#41;&#44; 10&#46;7&#37; in phase 2 &#40;2002&#8211;2004&#41;&#44; 8&#46;8&#37; in the phase 3 &#40;2005&#8211;2008&#41;&#44; 6&#46;8&#37; in phase 4 &#40;2009&#8211;2011&#41; and 8&#46;7&#37; in phase 5 &#40;2012&#8211;2015&#41;&#46; The prevalence of HCV infection in our HD unit&#44; with a mean time in dialysis of 82&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>78&#46;7 months was 10&#37;&#44; which is slightly higher than that observed in DOPPS phase 5&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Prior to 2011&#44; standard HCV treatment was based on pegylated interferon &#40;PegINF&#41; or the combination of PegIFN and RBV&#44; which resulted in SVR rates of 40&#8211;50&#37;&#44; although their significant adverse effects and low rate of SVR&#44; limited their widespread use&#46; Despite the relatively good results in terms of efficacy in patients on HD treated with PegIFN and RBV&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> the use of this therapy was hampered by the significantly high number of adverse events observed in this subpopulation&#46; A study by our group<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">22</span></a> showed that up to 60&#37; of patients on HD treated with an IFN-based therapy early discontinued treatment due to adverse events &#40;including hematological disorders and infections&#41;&#46; This explains the low applicability of IFN-based therapies in patients on HD as shown in the DOPPS study&#44; in which only 1&#46;5&#37; of the patients included received antiviral therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The development of IFN-free therapies with different combinations of DAAs has revolutionized the treatment of patients in HD&#46; There are 3 clinical trials specifically designed to evaluate the safety and efficacy of antiviral therapy in patients with chronic kidney disease stages 4 and 5&#46; The RUBY-1<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> trial evaluated the 3D combination with or without RBV in 20 genotype 1-infected patients with CKD stages 4 and 5&#46; Overall&#44; 90&#37; &#40;18 out of the 20 patients&#41; achieved SVR12&#46; Anemia was the most common adverse event&#46; In the second part of the study&#44; 18 genotype 1a and 4 infected patients &#40;normally requiring RBV&#41; received the 3D or 2D combination without RBV and all of them achieved SVR&#46; In the C-SURFER<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">13</span></a> study&#44; 224 genotype 1 infected patients were randomly assigned to receive the combination of Grazoprevir and Elbasvir once daily for 12 weeks or placebo &#40;deferred treatment&#41;&#46; In the full set analysis&#44; 94&#37; and 95&#37; of patients in the immediate and the deferred treatment groups&#44; respectively&#44; achieved SVR12&#46; More recently&#44; the combination of Glecaprevir and Pibrentasvir administered for 12 weeks to 104 patients infected with different HCV genotypes and CKD stages 4 and 5 achieved an SVR of 100&#37; with excellent safety results&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">14</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Similar to the results of clinical trials or real life cohorts&#44;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">12&#44;23&#44;24</span></a> we obtained excellent results with the different DAAs combinations administered to our cohort&#46; Most of our patients received the 3D combination for 12 weeks and all of them achieved SVR&#46; Only one patient &#40;genotype 1a&#41; required RBV and prolonged treatment duration &#40;24 weeks&#41; because of the presence cirrhosis&#46; Despite Sofosbuvir is currently not approved for the treatment of patients with a glomerular filtration rate<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#44; 3 of our patients &#40;infected with genotype 2 and 3&#41; with no other treatment options received Sofosbuvir in combination with Daclatasvir for 12 or 24 weeks with excellent results in terms of efficacy and safety&#46; This is similar to what has been observed in small series of cases published recently evaluating different combinations of Sofosbuvir-based regimes in which SVR rate ranged between 67&#37; and 100&#37; depending on the dose of Sofosbuvir &#40;standard dose of 400<span class="elsevierStyleHsp" style=""></span>mg per day vs&#46; 400<span class="elsevierStyleHsp" style=""></span>mg every other day or 200<span class="elsevierStyleHsp" style=""></span>mg per day&#41; and the additional drug &#40;RBV vs&#46; other DAA&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">20&#44;25&#8211;27</span></a> More importantly&#44; despite the concerns of using Sofosbuvir in patients on HD due to the potential side effects secondary to GS331007 &#40;principal metabolite of Sofosbuvir&#41; accumulation&#44; we and others did not observe serious adverse events in patients on HD receiving this drug&#46; However&#44; more data are needed to confirm these results and to recommend the widespread use of Sofosbuvir in patients on HD&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Interestingly&#44; we observed an improvement in the control of anemia with a significant increase in hemoglobin and hematocrit levels&#44; and a tendency toward a decrease in the dose of intravenous iron during the 12 months after treatment discontinuation&#46; The explanation for this phenomenon is unknown&#46; However&#44; one can speculate that elimination of HCV infection could improve iron metabolism and response to erythropoiesis due to a decrease in systemic inflammation&#46; The role of HCV infection on iron metabolism in patients on HD is controversial&#46; A study by Abdalla et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> showed that HCV positive patients on HD had higher EPO requirement &#40;49&#46;6 vs&#46; 14&#46;4 units&#47;kg&#47;dialysis&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41; and low hemoglobin levels &#40;10&#46;5 vs&#46; 11&#46;2<span class="elsevierStyleHsp" style=""></span>g&#47;dL&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41; as compared to HCV negative patients&#46; However&#44; more recent studies have shown opposite results&#46; For example&#44; Khurana et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a> found that HCV positive patients required low EPO dose as compared to HCV negative counterparts &#40;253 vs&#46; 460 units&#47;kg&#47;month&#41; with no significant differences in other parameters&#46; In addition&#44; the number of patients not requiring EPO was significantly higher among HCV positive patients&#46; Since&#44; CKD-related anemia is associated with significant morbidity and mortality&#59; the improvement in the control of anemia could improve cardiovascular risk&#44; long-term survival&#44; and quality of life&#46; Obviously&#44; the limited number of patients included in the study and the short follow-up duration &#40;up to 1 year after treatment discontinuation&#41; preclude us to draw a formal conclusion&#46; However&#44; new studies&#44; with longer follow-up of treated patients&#44; would be interesting to confirm this hypothesis&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In order to prevent HCV transmission in HD units&#44; KDIGO &#40;Kidney Disease Improving Global Outcomes&#41; guidelines recommend to strictly adhering to infection-control procedures&#46; However&#44; isolation of HCV infected patients or using specifically dedicated machines for these patients is not recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">29</span></a> In our unit&#44; we follow these recommendations but all HCV positive patients are located in dialysis shifts with a specific nurse devoted to their care following the international recommendations to avoid blood-borne pathogens&#46; There is no information on the literature regarding the management of HD patients achieving SVR after antiviral therapy&#46; In our unit viral elimination&#44; at the time of SVR achievement &#40;3 months after the end of therapy&#41; patients are relocated to HCV negative dialysis shift&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Our study has several limitations&#44; including the low number of patients enrolled&#44; the absence of patients infected with less frequent genotypes&#44; and the lack of a standardized treatment for all patients due to the rapid evolution of antiviral treatments within the past few years&#46; However&#44; this is a proof of concept that HCV infection can be eliminated from HD units by treating all patients &#40;including patients with severe comorbidities&#41; by a multidisciplinary team of experts in the management of this subpopulation&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In conclusion&#44; with the incorporation of new DAAs it is possible to eradicate HCV from dialysis units&#46; The variety of therapeutic possibilities&#44; along with the high efficacy and good tolerance of these drugs allows treating and curing the whole dialysis population&#46; HCV elimination in HD units is a major breakthrough that should allow a zero incidence of hepatitis C infections&#46; Despite further research and validation is required&#44; it appears that HCV elimination is associated&#44; at individual level&#44; to an improvement in the control of anemia&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">MCL has received advisory fees from Janssen&#44; Abbvie&#44; Gilead&#44; MSD and BMS&#46; The other authors have declared no conflict of interest&#46;</p></span></span>"
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              "titulo" => "Study design and antiviral therapy"
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              "titulo" => "Monitoring"
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              "titulo" => "Effectiveness and tolerability of antiviral therapy"
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              "titulo" => "Impact of therapy on clinical and analytical outcomes"
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    "fechaRecibido" => "2018-06-07"
    "fechaAceptado" => "2018-07-29"
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          "clase" => "keyword"
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            0 => "Elimination"
            1 => "Hemodialysis"
            2 => "Hepatitis C virus"
            3 => "Sustained virologic response"
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            0 => "Eliminaci&#243;n"
            1 => "Hemodi&#225;lisis"
            2 => "Virus de la hepatitis C"
            3 => "Respuesta viral sostenida"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">In the interferon era&#44; the treatment of hepatitis C virus &#40;HCV&#41; infection in patients on haemodialysis &#40;HD&#41; was limited due to the significant number of treatment-related adverse events &#40;AEs&#41;&#46; Direct-acting antivirals &#40;DAAs&#41; have demonstrated their efficacy and safety in the treatment of HCV in patients with advanced chronic kidney disease on haemodialysis&#46; The objective of the study was to evaluate the success in eliminating HCV infection from our dialysis unit using DAAs&#44; and to assess the impact of HCV elimination on clinical and analytical outcomes&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This is a prospective&#44; interventional&#44; single-center study at Hospital Cl&#237;nic de Barcelona&#46; All HCV-RNA positive patients who received antiviral therapy with DAAs within a 3-year period &#40;2014&#8211;2017&#41; were analyzed &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41;&#46; Data on virologic response&#44; adverse events&#44; and biochemical and hematological parameters during and after DAA therapy were analyzed&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">All patients achieved sustained virologic response &#40;SVR&#41; and only 40&#37; of patients presented with mild AEs&#46; None of the patients presented with HCV reinfection after a 1-year follow-up period&#44; and thus HCV was eliminated from our HD unit&#46; SVR was associated with a significant increase in hemoglobin and hematocrit&#44; and a tendency toward the need for lower doses of iron supplementation with no changes in darbepoetin dose&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">HCV infection can be safely eliminated from HD units with the use of DAAs&#44; preventing new infections in patients and healthcare staff&#46; In the short term&#44; the achievement of SVR is associated with an improvement in the control of anemia&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">En la &#233;poca del interfer&#243;n&#44; el tratamiento del virus de la hepatitis C &#40;VHC&#41; en pacientes en hemodi&#225;lisis &#40;HD&#41; se ve&#237;a limitado por la presencia de efectos adversos relacionados con el tratamiento&#46; Los agentes antivirales directos &#40;AAD&#41; han demostrado ser seguros y eficaces en el tratamiento del VHC en pacientes con insuficiencia renal cr&#243;nica en hemodi&#225;lisis&#46; El objetivo del estudio fue evaluar el &#233;xito en eliminar la infecci&#243;n por VHC de nuestra unidad de di&#225;lisis con el uso de AAD&#44; y determinar el impacto cl&#237;nico y anal&#237;tico de la curaci&#243;n de la infecci&#243;n&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Para ello se realiz&#243; un estudio prospectivo de intervenci&#243;n en el Hospital Clinic de Barcelona y su centro de di&#225;lisis&#46; Se incluyeron todos los pacientes &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#41; con ARN-VHC positivo que recibieron tratamiento antiviral con AAD durante un periodo de 3 a&#241;os &#40;2014-2017&#41;&#46; Se analizaron los datos de respuesta virol&#243;gica&#44; efectos adversos y par&#225;metros hematol&#243;gicos y bioqu&#237;micos durante y despu&#233;s del tratamiento&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Todos los pacientes alcanzaron una respuesta viral sostenida &#40;RVS&#41; y solo una 40&#37; presentaron efectos adversos leves&#46; Ning&#250;n paciente present&#243; reinfecci&#243;n por el VHC y por ello tras un a&#241;o de seguimiento se consider&#243; la eliminaci&#243;n del VHC de nuestra unidad de di&#225;lisis&#46; La RVS se asoci&#243; con aumento significativo de la hemoglobina y el hematocrito&#44; y una tendencia a la necesidad de una dosis m&#225;s baja de suplemento de hierro sin cambios en la dosis de darbepoetina&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Con la utilizaci&#243;n de AAD&#44; la infecci&#243;n por el VHC puede ser eliminada de forma segura de las unidades de di&#225;lisis&#44; previniendo la transmisi&#243;n de la infecci&#243;n a pacientes y personal sanitario&#46; A corto plazo&#44; la RVS se asoci&#243; con una mejor&#237;a en el control de la anemia&#46;</p></span>"
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            "apendice" => "<p id="par0135" class="elsevierStylePara elsevierViewall">The following is the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0060"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flowchart of the patients with HCV infection detected in the HD unit&#46;</p>"
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        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Evolution of hematological parameters after treatment discontinuation&#46; Data were analyzed using one-way repeated measures ANOVA&#46; EOT&#58; End of therapy&#44; SVR12&#58; 12 weeks after treatment discontinuation&#44; SVR24&#58; 24 weeks after treatment discontinuation&#44; SVR48&#58; 48 weeks after treatment discontinuation&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age&#44; years &#40;mean</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#177;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">53&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Gender male&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;65&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Diabetes mellitus&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;25&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Cirrhosis&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;40&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Coinfection&#44; n&#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>HIV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;15&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>HBV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Genotype&#44; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;60&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>2c&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>3a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;10&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>4a&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Previous antiviral treatment&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Current antiviral treatment&#44; n &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Asunaprevir&#47;Daclatasvir&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;10&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Grazoprevir&#47;Elbasvir&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;25&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Paritaprevir&#47;Ombitasvir&#47;Dasabuvir&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;40&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Paritaprevir&#47;Ombitasvir&#47;Dasabuvir&#47;Ribavirin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Simeprevir&#47;Daclatasvir&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sofosbuvir&#47;Daclatasvir&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;15&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Adverse effects&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;40&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics of the patients included in the study&#46;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Data are expressed as median &#40;range&#41;&#46; EOT&#58; end of therapy&#44; SVR12&#58; 12 weeks after treatment discontinuation&#44; SVR24&#58; 24 weeks after treatment discontinuation&#44; SVR48&#58; 48 weeks after treatment discontinuation&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Hemoglobin &#40;g&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Hematocrit &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">EV iron dose &#40;mg&#47;week&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Darbepoetin dose &#40;mcg&#47;week&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ERI IU&#47;week&#47;kg&#47;g Hb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Ferritin &#40;&#956;g&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TSI &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Baseline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">112&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">49&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>38&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#46;06<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">489<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>301&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">EOT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">110&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">34<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">57&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>36&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#46;44<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">305<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>132&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SVR12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">115&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>35&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8&#46;86<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">310<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>147&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SVR24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">117<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">61&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>31&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#46;02<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">339<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>171&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SVR48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">117&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>25&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#46;63<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">390<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>232&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">p</span>-Value<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;048&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;064&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;138&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;128&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;238&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;707&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "etiqueta" => "&#42;"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Hematological parameters during and after treatment discontinuation&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patient number&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adverse event&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arthralgia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Heartburn&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diarrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diarrhea and pruritus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pruritus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pruritus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient 20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information
ISSN: 02105705
Original language: English
DOI:10.1016/j.gastrohep.2018.07.015
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