Outcomes for Cirrhotic Patients with Hepatitis C Virus 1b Treated with Asunaprevir and Daclatasvir Combination

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"documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Ann Hepatol. 2017;16:727-33" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 295 "formatos" => array:3 [ "EPUB" => 16 "HTML" => 186 "PDF" => 93 ] ] "en" => array:10 [ "idiomaDefecto" => true "titulo" => "Treatment of Chronic HCV Infection with the New Direct Acting Antivirals (DAA): First Report of a Real World Experience in Southern Brazil" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "727" "paginaFinal" => "733" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Hoel Sette-Jr, Hugo Cheinquer, Fernando H. Wolff, Alexandre de Araujo, Silvia Coelho-Borges, Silvia R.P. Soares, Mauricio F.A. Barros" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Hoel" "apellidos" => "Sette-Jr" ] 1 => array:2 [ "nombre" => "Hugo" "apellidos" => "Cheinquer" ] 2 => array:2 [ "nombre" => "Fernando H." "apellidos" => "Wolff" ] 3 => array:2 [ "nombre" => "Alexandre" "apellidos" => "de Araujo" ] 4 => array:2 [ "nombre" => "Silvia" "apellidos" => "Coelho-Borges" ] 5 => array:2 [ "nombre" => "Silvia R.P." "apellidos" => "Soares" ] 6 => array:2 [ "nombre" => "Mauricio F.A." "apellidos" => "Barros" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119304314?idApp=UINPBA00004N" "url" => "/16652681/0000001600000005/v1_201905301208/S1665268119304314/v1_201905301208/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "titulo" => "Outcomes for Cirrhotic Patients with Hepatitis C Virus 1b Treated with Asunaprevir and Daclatasvir Combination" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "734" "paginaFinal" => "741" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Akihiro Tamori, Hoang Hai, Sawako Uchida-Kobayashi, Masaru Enomoto, Ritsuzo Kozuka, Hiroyuki Motoyama, Etsushi Kawamura, Atsushi Hagihara, Yuga Teranishi, Kanako Yoshida, Hiroyasu Morikawa, Yoshiki Murakami, Norifumi Kawada" "autores" => array:13 [ 0 => array:4 [ "nombre" => "Akihiro" "apellidos" => "Tamori" "email" => array:1 [ 0 => "atamori@med.osaka-cu.ac.jp" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] ] ] 1 => array:2 [ "nombre" => "Hoang" "apellidos" => "Hai" ] 2 => array:2 [ "nombre" => "Sawako" "apellidos" => "Uchida-Kobayashi" ] 3 => array:2 [ "nombre" => "Masaru" "apellidos" => "Enomoto" ] 4 => array:2 [ "nombre" => "Ritsuzo" "apellidos" => "Kozuka" ] 5 => array:2 [ "nombre" => "Hiroyuki" "apellidos" => "Motoyama" ] 6 => array:2 [ "nombre" => "Etsushi" "apellidos" => "Kawamura" ] 7 => array:2 [ "nombre" => "Atsushi" "apellidos" => "Hagihara" ] 8 => array:2 [ "nombre" => "Yuga" "apellidos" => "Teranishi" ] 9 => array:2 [ "nombre" => "Kanako" "apellidos" => "Yoshida" ] 10 => array:2 [ "nombre" => "Hiroyasu" "apellidos" => "Morikawa" ] 11 => array:2 [ "nombre" => "Yoshiki" "apellidos" => "Murakami" ] 12 => array:2 [ "nombre" => "Norifumi" "apellidos" => "Kawada" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Correspondence and reprint request:" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0015" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1112 "Ancho" => 1471 "Tamanyo" => 147065 ] ] "descripcion" => array:1 [ "en" => "Change from baseline ALT levels during ASV + DCV treatment in cirrhot-ic and non-cirrhotic groups. * Treatment was stopped due to ALT elevation." ] ] ] "textoCompleto" => "IntroductionChronic hepatitis C (CHC) stemming from infection with the hepatitis C virus (HCV) affects ~170 million people worldwide and is the most common cause of chronic liver disease. Of all HCV-infected individuals, 20-30% eventually develop liver cirrhosis or hepatocellular carcinoma (HCC).<a class="elsevierStyleCrossRef" href="#bib0010">1</a> The elimination of HCV is important for preventing HCC, particularly in aged patients with advanced fibrosis or CHC.<a class="elsevierStyleCrossRefs" href="#bib0015">2,3</a>Since 2010, direct-acting antiviral (DAA) regimens with or without interferon (IFN) have been evaluated and approved for anti-HCV therapy. In Japan, the protease inhibitors telaprevir, simeprevir, and vaniprevir have been approved for use as DAA combination therapy with pegylated interferon and ribavirin.<a class="elsevierStyleCrossRefs" href="#bib0025">4-7</a> Asunaprevir (ASV) and daclatasvir (DCV) combination therapy was developed as the first IFN-free anti-HCV therapeutic regimen in 2014. To date, this regimen has been approved by regulatory authorities in several countries across the Asia-Pacific region, including Korea, Taiwan, Australia, Singapore, and Mexico. In a phase III clinical trial in Japan, 168 (91.3%) of 214 patients without resistance-associated substitutions (RASs) at Y93 in the nonstructural protein (NS) 5A achieved sustained viral response (SVR).<a class="elsevierStyleCrossRef" href="#bib0045">8</a> On the other hand, only 13 (43.3%) of 30 patients with RAS at Y93 achieved SVR. Therefore, the Japanese guidelines for HCV management recommend ASV + DCV combination therapy for patients without RAS at NS5A of HCV genotype 1b.<a class="elsevierStyleCrossRef" href="#bib0050">9</a> In this phase III trial, 20 (90.9%) of 22 compensated cirrhotic patients achieved SVR. In a global phase III trial outside Japan, SVR12 was achieved by 171 (84%) of 206 cirrhotic patients and by 371 (85%) of 437 non-cirrhotic patients.<a class="elsevierStyleCrossRef" href="#bib0055">10</a> There was no significant incidence of serious adverse effects (AEs). However, the mean age of enrolled patients was 5-6 years younger in the global study than in the Japanese trial. In addition, these phase III trials excluded cirrhotic or non-cirrhotic patients with a history of curative treatment for HCC. DAA therapy has now been approved for patients with a past history of HCC in Japan. It is necessary to evaluate the preventive effects of ASV + DCV therapy on the recurrence of HCC.This study evaluated the anti-HCV effect and safety of ASV + DCV combination therapy for compensated cir-rhotic patients compared to non-cirrhotic patients. In addition, the development of HCC and liver function after therapy were evaluated in cirrhotic patients.Material and MethodsPatientsBefore commencing treatment, we checked the RAS in NS5A of 350 patients with HCV genotype 1b (not shown). A total of 145 patients without RAS on L31 and Y93 within the NS5A domain were enrolled for treatment with ASV + DCV combination therapy, consisting of 49 hepatic cir-rhotic patients and 96 non-cirrhotic patients. Hepatic cirrhosis was defined as histological examination F4 or > 15.0 kPa according to transient elastography. The enrolled patients were aged 40-86 years old and were chronically infected with HCV genotype 1b with a serum HCV RNA viral load > 3 log copies/mL at baseline. Patients were excluded if they had medical contraindications for ASV and DCV, a history of DAA use, a history of drug use, decom-pensated cirrhosis, a Child-Pugh score > 6, or evidence of other significant liver diseases, including hepatitis B virus, autoimmune liver diseases, alcoholic liver disease, and viable HCC. None of the patients showed evidence of infection by human immunodeficiency virus (HIV). This study was performed in accordance with the 1975 Declaration of Helsinki (2004 version), and written informed consent was obtained from all patients prior to treatment. The study protocol was approved by the Ethics Committee of each hospital and by the Ethics Committee of Osaka City University Graduate School of Medicine (No. 2905). The trial was registered in UMIN (No. 000015806).Study designThe patients were treated with 100 mg ASV (Sun-vepra®, Bristol-Myers Squibb, Tokyo, Japan) twice per day plus 60 mg DCV (Daklinza®, Bristol-Myers Squibb) once daily for 24 weeks. A total of 110 (76%) of the 145 patients were admitted to the hospital for 3-7 days at initiation and were educated regarding DAA therapy by a hospital pharmacist. A serum liver function test and an imaging test were performed regularly for 1 year from the end of treatment (EOT), in addition to the evaluation of serum HCV viral load.Virological evaluationsHCV-RNA was determined by TaqMan HCV assay (COBAS® TaqMan® HCV assay, Roche Molecular Diagnostics, Tokyo, Japan) with a lower limit of quantification of 15 IU/mL and an upper limit of quantification of 6.9 x 107 IU/mL (1.2-7.8 log IU/mL). The HCV genotype was determined using an HCV genotype primer kit (Institute of Immunology Co., Ltd., Tokyo, Japan). RAS in the NS3/4A protease and the NS5A were evaluated using the direct sequencing method according to a previously reported protocol.<a class="elsevierStyleCrossRef" href="#bib0060">11</a> Resistance analysis focused on amino acid polymorphisms Q80, R155, A156, D168, and V170 within NS3/4 A and of L28, R30, L31, Q54, P58, Q62, A92, and Y93 within the NS5A domain.Virological response to the therapy was defined as follows: relapse showing undetectable HCV-RNA at EOT but detectable HCV RNA after EOT and re-elevation of HCV RNA at any time during treatment after a virological response (breakthrough). Patients in whom HCV-RNA remained stable during treatment were defined as non-responders.EvaluationsThe rate of SVR24, defined as undetectable HCV-RNA at 24 weeks after completion of treatment, was used to evaluate primary efficacy. In addition, the improvement of liver function and HCC development were used as secondary evaluations after treatment. During the follow-up period, clinical, biochemical, and quantitative serum HCV-RNA assessments were evaluated at 1- to 3-month intervals. Safety evaluations included adverse event reporting, laboratory test values, and physical examinations. All methods used for assessing treatment efficacy were defined according to previously published guidelines.<a class="elsevierStyleCrossRef" href="#bib0065">12</a>SNP genotypingWe examined genetic polymorphisms in the interleukin 28B (IL28B) gene in patients that consented to genetic anal-ysis.<a class="elsevierStyleCrossRef" href="#bib0070">13</a> Whole blood was collected from patients and centri-fuged to separate the buffy coat. Genomic DNA was extracted from the buffy coat using a QIAamp® DNA Blood Midi Kit (Qiagen, Maryland, Germantown, MD). Genetic polymorphisms in IL28B rs8099917 and rs12979860 were genotyped by TaqMan SNP Genotyping Assay with the 7500 Fast Real-Time PCR System (Applied Biosystems, Foster City, CA). All samples were also subjected to direct sequencing to confirm the genotype. The primers and procedures used were as described previously.<a class="elsevierStyleCrossRefs" href="#bib0070">13,14</a>Statistical analysisData analyses were conducted using JMP software (ver. 9.0; SAS Institute, Cary, NC). Differences between groups were evaluated by Wilcoxon's two-sample test for numerical variables or Fisher's exact test for categorical variables. Variables with p < 0.1 in univariate analyses were subjected to stepwise multivariate logistic regression analyses. In the two-tailed test, p < 0.05 was taken to indicate statistical significance.RESULTSPatients at baselineThe clinical background of 49 hepatic cirrhotic and 96 non-cirrhotic patients are shown in <a class="elsevierStyleCrossRef" href="#t0010">table 1</a>. The cirrhotic group contained 21 females and 28 males, and the non-cir-rhotic group had 41 females and 54 males (p = 0.79). The median age was 71 years old (range: 48-86 years old) in the cirrhotic group, and 71 years old (range: 40-84 years old) in the non-cirrhotic group (p = 0.74). Previous IFN-based therapies were performed in 30 patients (61%) in the cirrhotic group and 49 (51%) in the non-cirrhotic group. The cirrhotic group had 14 (29%) patients with curative treatment for HCC, whereas the non-cirrhotic group had 8 (8%) patients with curative treatment for HCC (p < 0.02). There were significant differences in WBC, hemoglobin, platelet counts, and AFP levels at baseline between the cirrhotic and non-cirrhotic groups. The mean HCV-RNA level was 6.1 ± 0.5 log copies/mL in the cirrhotic group and 6.1 ± 0.8 log copies/mL in the non-cirrhotic group (p = 0.31). RASs in the HCV NS3/4A gene were detected in 15 (31%) of 49 patients in the cirrhotic group: Q80L, 2, D168E, 3, and V170I, 15. RASs were detected in 33 (34%) of 96 patients in the non-cirrhotic group: Q80L, 4, Q80R, 2, R155K, 1, D168E, 2, and V170I, 30. No differences in the distribution of the IL28B genotypes were detected between the two groups.<elsevierMultimedia ident="t0010"></elsevierMultimedia>Treatment responses in the cirrhotic and non-cirrhotic groupsRVR rates were 79% (38/48) in the cirrhotic group and 86% (78/91) in the non-cirrhotic group (p = 0.45). The rates at the EOT were 98% (48/49) in the cirrhotic group and 98% (94/96) in the non-cirrhotic group (p = 0.55). The SVR24 rates were 96% (47/49) in the cirrhotic group and 96% (91/95) in the non-cirrhotic group (p = 0.69). There were no significant differences in the treatment response rate between the two groups (<a class="elsevierStyleCrossRef" href="#f0010">Figure 1</a>). Viral breakthrough occurred in one patient in the cirrhotic group and two patients in the non-cirrhotic group (p = 0.55). At baseline RASs at D168E and V170I in the HCV NS3/4A were detected in two (31%) of three patients with viral breakthrough. Viral relapse occurred in one patient in the cirrhotic group and two patients in the non-cirrhot-ic group (p = 0.55). In three patients with relapse, ASV + DCV therapy was stopped due to adverse effects. At baseline RASs in the HCV NS3/4A were not detected in all of patients with viral relapse.<elsevierMultimedia ident="f0010"></elsevierMultimedia>Adverse events and treatment discontinuationTreatment was discontinued for various reasons in the cirrhotic group, as follows (one patient each): ALT elevation, hepatic coma, institutional pneumonia, severe bronchitis, and HCC development. In the non-cirrhotic group, treatment was discontinued due to ALT elevation in five patients, prothrombin time elongation in two patients, trauma in one patient, and self-discontinuation in one patient.Grade III/IV adverse events occurred more frequently in the cirrhotic group (10/49; 20.4%) than in the non-cir-rhotic group (10/96; 10.4%) (p = 0.099). ALT elevation is an AE of DCV/ASV therapy, particularly in Japanese patients. The ALT level was elevated by more than twice the normal upper limit in 9 of 49 cirrhotic patients and 19 of 96 non-cirrhotic patients. There were no differences in the incidence of ALT elevation between the two groups (<a class="elsevierStyleCrossRef" href="#t0015">Table 2</a>). DAA therapy was stopped in one cirrhotic patient and five non-cirrhotic patients due to ALT elevation (<a class="elsevierStyleCrossRef" href="#f0015">Figure 2</a>). One non-cirrhotic patient died after ASV + DCV therapy due to events that were not related to the treatment.<elsevierMultimedia ident="t0015"></elsevierMultimedia><elsevierMultimedia ident="f0015"></elsevierMultimedia>Prognosis of liver function and development of HCC after therapy in cirrhotic patientsFirst, liver biochemical markers were evaluated in 47 cirrhotic patients that achieved SVR. Compared to the baseline, ALT and AFP levels were significantly decreased at EOT, post-24th week, and post-48th week (p < 0.01). In addition, albumin levels were gradually increased after ASV + DCV therapy (<a class="elsevierStyleCrossRef" href="#f0020">Figure 3</a>).<elsevierMultimedia ident="f0020"></elsevierMultimedia>In all, 22 patients had received curative treatment for HCC before ASV + DCV therapy. After confirming the lack of HCC recurrence by contrast computed tomography or magnetic resonance imaging, ASV + DCV therapy was started. Over 48 weeks from the end of anti-HCV therapy, recurrence of HCC was observed in 6 (43%) of 14 cirrhotic, and 1 (12.5%) of 8 non-cirrhotic patients. On the other hand, HCC developed in 2 (5.7%) of 35 cirrhot-ic, and 1 (1.2%) of 88 non-cirrhotic patients (<a class="elsevierStyleCrossRef" href="#f0025">Figure 4</a>). HCC recurrence and occurrence were observed more frequently in the cirrhotic group than in the non-cirrhotic group.<elsevierMultimedia ident="f0025"></elsevierMultimedia>DiscussionIn the present study, 96% of cirrhotic and non-cirrhotic patients without RAS in NS5A achieved SVR after ASV + DCV therapy. RAS-oriented ASV + DCV therapy was also reasonable for HCV genotype 1b patients with cirrhosis. Previous reports have indicated SVR rates of 88.3-93.7% in patients without RAS in NS5A.<a class="elsevierStyleCrossRefs" href="#bib0080">15-17</a> The anti-viral effect observed in our study was slightly higher than those results. In our study, 76% patients started treatment at admission, and were instructed regarding DAA by a hospital pharmacist. Only 2 (1.7%) of 115 patients did not achieve SVR in the admitted group, and 4 (11%) of 35 patients without admission failed to achieve SVR (p = 0.039). These results suggest that admission with commencement of DAA be recommended, particularly in Japan.On the other hand, AEs (adverse events) of grade III/IV occurred more frequently in cirrhotic patients than in non-cirrhotic patients during treatment. Elevation of ALT was a unique AE associated with ASV + DCV therapy. There were no differences in the incidence of serious ALT elevation between cirrhotic and non-cirrhotic groups. Bleeding in the digestive tract and hepatic coma were serious AEs seen only in the cirrhotic group. Compared to the Japanese phase III trial, there were some differences in AEs in the present study. These differences may have been due to the characteristics of the enrolled patients in terms of their age, gender, cirrhosis status, and history of HCC. Taken together, these results suggest that careful management is necessary for cirrhotic patients before and during ASV + DCV therapy.A follow-up study showed that ALT levels and AFP levels decreased significantly after EOT in cirrhotic patients that achieved SVR. In addition, serum levels of albumin and platelet count significantly increased compared to baseline measurements. Our data are consistent with previous reports. Miyaki, et al. showed that serum fibrosis markers are improved in SVR patients.<a class="elsevierStyleCrossRef" href="#bib0095">18</a> Mandorfer, et al. reported that DAA therapy decreases portal pressure in SVR patients with moderate hepatic fibrosis as determined by measuring hepatic venous pressure gradient.<a class="elsevierStyleCrossRef" href="#bib0100">19</a> These data suggest that the elimination of HCV by DAA therapy improved liver function in cirrhotic patients.On the other hand, the incidence rates of HCC development and recurrence were higher in cirrhotic patients. Conti, et al. reported that HCC was detected during 24-weeks of follow-up in 17 (29%) of 59 patients with previous HCC and 9 (3%) of 285 cirrhotic patients without HCC.<a class="elsevierStyleCrossRef" href="#bib0105">20</a> Our observations are in line with those of other previous studies.<a class="elsevierStyleCrossRef" href="#bib0110">21</a> Both the observation period and the incidence of HCC in our study were double those in these previous studies. Previous Japanese studies of IFN-based therapy showed that age and fibrosis at baseline were closely related to HCC development in SVR patients.<a class="elsevierStyleCrossRefs" href="#bib0020">3,22</a> Although the reasons for the high incidence of HCC development in patients treated with DAA are not clear, greater age and more-advanced fibrosis might be related to the development of HCC.IFN-based therapy without DAA showed a preventive effect on the development of HCC in patients with HCV, even in those who did not achieve SVR. It was speculated that IFN had two effects, i.e., antivirus and antitumor effects. On the other hand, DAAs were designed as specific inhibitors of HCV and did not have direct antitumor sup-pressive effects. Minami, et al. compared the rate of HCC development between a DAA treatment group, an IFN-based therapy group, and a control group. The rate of early recurrence was not different between the three groups.<a class="elsevierStyleCrossRef" href="#bib0120">23</a> It is important to monitor cirrhotic patients that achieve SVR with DAA therapy.The present study had several limitations. First, the number of patients enrolled in the study was low, although the number was greater than in the phase III clinical trial. In September 2015, a 12-week IFN-free regimen was approved for HCV genotype 1 in Japan.<a class="elsevierStyleCrossRefs" href="#bib0125">24,25</a> It is difficult to implement a study in a larger cohort because patients prefer therapies with shorter durations. Second, there were no decompensated cirrhotic patients in the present study, as anti-HCV therapy is not approved for such patients in Japan. Finally, the follow-up period was insufficient to evaluate prognoses in cirrhotic patients with SVR. SVR is an important process but is not the goal of treatment in cases of chronic viral liver disease. It is necessary to evaluate long-term prognoses in cirrhotic patients with HCV, including the prevention of HCC development and the prevention of hepatic failure.Taken together, our findings suggest that ASV + DCV therapy can achieve a high SVR rate in Japanese cirrhotic patients with NS5A wild-type HCV genotype 1b and also improve liver function, including albumin and AFP levels. However, AEs occur frequently in cirrhotic patients, particularly the recurrence and occurrence of HCC after therapy.AcknowledgmentsThis study was supported in a part by Japan Society for the Promotion of Science grant 15k09019 (AT). We would like to thank Ms. Yoko Yasuhara, Ms. Tomoko Hirano and Ms. Sanae Deguchi for collecting the data.Abbreviations<ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0010">•AEs: adverse events.</li><li class="elsevierStyleListItem" id="u0015">•ALT: alanine aminotransferase.</li><li class="elsevierStyleListItem" id="u0020">•EOTR: end of treatment response.</li><li class="elsevierStyleListItem" id="u0025">•HCC: hepatocellular carcinoma.</li><li class="elsevierStyleListItem" id="u0030">•HCV: hepatitis C virus.</li><li class="elsevierStyleListItem" id="u0035">•IL28B: interleukin 28 B.</li><li class="elsevierStyleListItem" id="u0040">•RAS: resistance-associated substitution.</li><li class="elsevierStyleListItem" id="u0045">•RVR: rapid virological responders.</li><li class="elsevierStyleListItem" id="u0050">•SVR: sustained viral response.</li><li class="elsevierStyleListItem" id="u0055">•UNL: upper normal limit.</li></ul>Conflicts of InterestAll authors declare that we have nothing to disclose regarding funding or conflict of interest with respect to the study reported in this manuscript." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1197552" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abs0010" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abs0015" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abs0020" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abs0025" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1116238" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "s0010" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "s0015" "titulo" => "Material and Methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "s0020" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "s0025" "titulo" => "Study design" ] 2 => array:2 [ "identificador" => "s0030" "titulo" => "Virological evaluations" ] 3 => array:2 [ "identificador" => "s0035" "titulo" => "Evaluations" ] 4 => array:2 [ "identificador" => "s0040" "titulo" => "SNP genotyping" ] 5 => array:2 [ "identificador" => "s0045" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "s0050" "titulo" => "RESULTS" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0055" "titulo" => "Patients at baseline" ] 1 => array:2 [ "identificador" => "s0060" "titulo" => "Treatment responses in the cirrhotic and non-cirrhotic groups" ] 2 => array:2 [ "identificador" => "s0065" "titulo" => "Adverse events and treatment discontinuation" ] 3 => array:2 [ "identificador" => "s0070" "titulo" => "Prognosis of liver function and development of HCC after therapy in cirrhotic patients" ] ] ] 5 => array:2 [ "identificador" => "s0075" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "s0080" "titulo" => "Acknowledgments" ] 7 => array:2 [ "identificador" => "s0085" "titulo" => "Abbreviations" ] 8 => array:2 [ "identificador" => "s0090" "titulo" => "Conflicts of Interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-02-08" "fechaAceptado" => "2017-03-23" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1116238" "palabras" => array:4 [ 0 => "Adverse events" 1 => "Hepatocellular carcinoma" 2 => "Resistance-associated substitution" 3 => "Sustained viral response" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundThe efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). Material and methodsA total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy. The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks. The primary endpoint was SVR 24 weeks after completing treatment. In addition, we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment (EOT). ResultsThe SVR24 rate was 96% (47/49) in the cirrhotic group and 96% (91/95) in the non-cirrhotic group (p = 0.69). During treatment, grade III/IV adverse events occurred more frequently in cir-rhotic patients (10/49; 20.4%) than in non-cirrhotic patients (10/96; 10.4%) (p = 0.099). After EOT, alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR. In addition, serum levels of albumin and platelet counts were significantly increased. On the other hand, the rates of HCC recurrence (43%) and development (7.4%) were higher in cirrhotic patients than in the non-cirrhotic patients (12.5% and 1.1%, respectively). ConclusionRAS-oriented asunaprevir/daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b. However, careful management is necessary in patients with cirrhosis." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abs0010" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abs0015" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abs0020" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abs0025" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 652 "Ancho" => 1002 "Tamanyo" => 96455 ] ] "descripcion" => array:1 [ "en" => "Rapid virological response (RVR), end-of-treatment response (EOTR), sustained virological response 12 weeks after completing treatment (SVR12), and SVR 24 weeks after completing treatment (SVR24) in cirrhot-ic and non-cirrhotic groups. RVR rates were 79% (38/48) in the cirrhotic group and 86% (78/91) in the non-cirrhotic group. EOT rates were 98% (48/ 49) in the cirrhotic group and 98% (94/96) in the non-cirrhotic group. SVR12 and SVR24 rates were 96% (47/49) and 96% (47/49) in the cirrhotic group, and 97% (92/95) and 96% (91/95) in the non-cirrhotic group, respectively. The rates at all-time points were not significantly different between the cir-rhotic and non-cirrhotic groups." ] ] 1 => array:7 [ "identificador" => "f0015" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1112 "Ancho" => 1471 "Tamanyo" => 147065 ] ] "descripcion" => array:1 [ "en" => "Change from baseline ALT levels during ASV + DCV treatment in cirrhot-ic and non-cirrhotic groups. * Treatment was stopped due to ALT elevation." ] ] 2 => array:7 [ "identificador" => "f0020" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1307 "Ancho" => 2083 "Tamanyo" => 144271 ] ] "descripcion" => array:1 [ "en" => "Changes in ALT, AFP, and serum levels of albumin and platelet count in cirrhotic patients that achieved SVR due to ASV + DCV therapy. Compared to baseline, ALT and AFP levels were significantly decreased after treatment. Albumin levels and platelet count were increased." ] ] 3 => array:7 [ "identificador" => "f0025" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 745 "Ancho" => 2083 "Tamanyo" => 119034 ] ] "descripcion" => array:1 [ "en" => "HCC recurrence and development during 1-year follow-up from the end of treatment. HCC recurred in 6 (43%) of 14 cirrhotic and 1 (12.5%) of 8 non-cirrhotic patients that had previous curative HCC therapy. HCC developed in 2 (7.4%) of 27 cirrhotic and 1 (1%) of 96 non-cirrhotic patients." ] ] 4 => array:7 [ "identificador" => "t0010" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "IFN: interferon. HCC: hepatocellular carcinoma. RFA: radiofrequency ablation. TACE: trans-catheter arterial chemoembolization. RAVs: resistant associated variants. WBC: white blood cell. Hb: hemoglobin. Plt: platelet. ALT: alanine aminotransferase. γ-GTP: gamma-glutamyl transpeptidase. AFP: alpha protein." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cirrhotic group \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-cirrhotic group \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Number of patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Male/female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21/28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42/54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.79 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Median age (range) years old \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 (48-86) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71 (40-84) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.74 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Body weight (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54.7 (40-95.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55.8 (38.1-94.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.73 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Previous IFN therapy ± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30/19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49/47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Curative treatment of HCC ± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14/35 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8/88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">< 0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Operation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.59 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RFA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TACE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL28B genotype (major/non-major/NT) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33/15/1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58/36/2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.50 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HCV RNA (log copies/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.9 (3.6-7.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.8 (3.4-7.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.31 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NS3/4A RAS (±) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Q80 (wild/L/R) D168 (wild/E) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">47/2/0 46/3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90/4/2 94/2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.3 0.34 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">WBC (/μL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3,900 (1,600-8,800) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5000 (2,300-10,400) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">< 0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hb (g/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.9 (8.3-16.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13.6 (9.8-16.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Plt (x104/μL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8.7 (3.7-20.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15.4 (7.1-29.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">< 0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T. Bil (mg/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.8 (0.3-2.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.7 (0.2-1.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.06 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Albumin (g/dL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.5 (2.5-4.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.9 (3.1-4.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">< 0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALT (IU/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48 (15-149) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 (9-231) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.21 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">γ-GTP (IU/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 (13-199) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">34 (11-752) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Creatinine (mg/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.7 (0.38-1.43) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.71 (0.41-1.83) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.84 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AFP (ng/L) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10.5 (1-375.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.8 (1-143.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">< 0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2045100.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Baseline characteristics of patients with L31 and Y93 in NS5A of HCV genotype 1b infection in cirrhotic and non-cirrhotic groups." ] ] 5 => array:7 [ "identificador" => "t0015" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cirrhotic (n = 49) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-cirrhotic (n = 96) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p value \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Discontinuation due to AEs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 (10.2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 (10.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.96 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serious AEs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 (20%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 (10.4%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.099 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ALT elevation > fivefold from UNL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bleeding in digestive tract \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatic coma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Elongation of prothrombin time \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Renal impairment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interstitial pneumonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bronchitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fever \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HCC recurrence \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diarrhea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Trauma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Other reasons for discontinuation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Viral breakthrough \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Self-discontinuation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2045099.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Adverse events with and without treatment discontinuation in cirrhotic 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Akihiro Tamori

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, Hoang Hai, Sawako Uchida-Kobayashi, Masaru Enomoto, Ritsuzo Kozuka, Hiroyuki Motoyama, Etsushi Kawamura, Atsushi Hagihara, Yuga Teranishi, Kanako Yoshida, Hiroyasu Morikawa, Yoshiki Murakami, Norifumi Kawada

Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan

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    "titulo" => "Outcomes for Cirrhotic Patients with Hepatitis C Virus 1b Treated with Asunaprevir and Daclatasvir Combination"
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Change from baseline ALT levels during ASV &#43; DCV treatment in cirrhot-ic and non-cirrhotic groups&#46; &#42; Treatment was stopped due to ALT elevation&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Introduction</span><p id="p0010" class="elsevierStylePara elsevierViewall">Chronic hepatitis C &#40;CHC&#41; stemming from infection with the hepatitis C virus &#40;HCV&#41; affects ~170 million people worldwide and is the most common cause of chronic liver disease&#46; Of all HCV-infected individuals&#44; 20-30&#37; eventually develop liver cirrhosis or hepatocellular carcinoma &#40;HCC&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">1</span></a> The elimination of HCV is important for preventing HCC&#44; particularly in aged patients with advanced fibrosis or CHC&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">Since 2010&#44; direct-acting antiviral &#40;DAA&#41; regimens with or without interferon &#40;IFN&#41; have been evaluated and approved for anti-HCV therapy&#46; In Japan&#44; the protease inhibitors telaprevir&#44; simeprevir&#44; and vaniprevir have been approved for use as DAA combination therapy with pegylated interferon and ribavirin&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">4-7</span></a> Asunaprevir &#40;ASV&#41; and daclatasvir &#40;DCV&#41; combination therapy was developed as the first IFN-free anti-HCV therapeutic regimen in 2014&#46; To date&#44; this regimen has been approved by regulatory authorities in several countries across the Asia-Pacific region&#44; including Korea&#44; Taiwan&#44; Australia&#44; Singapore&#44; and Mexico&#46; In a phase III clinical trial in Japan&#44; 168 &#40;91&#46;3&#37;&#41; of 214 patients without resistance-associated substitutions &#40;RASs&#41; at Y93 in the nonstructural protein &#40;NS&#41; 5A achieved sustained viral response &#40;SVR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">8</span></a> On the other hand&#44; only 13 &#40;43&#46;3&#37;&#41; of 30 patients with RAS at Y93 achieved SVR&#46; Therefore&#44; the Japanese guidelines for HCV management recommend ASV &#43; DCV combination therapy for patients without RAS at NS5A of HCV genotype 1b&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">9</span></a> In this phase III trial&#44; 20 &#40;90&#46;9&#37;&#41; of 22 compensated cirrhotic patients achieved SVR&#46; In a global phase III trial outside Japan&#44; SVR12 was achieved by 171 &#40;84&#37;&#41; of 206 cirrhotic patients and by 371 &#40;85&#37;&#41; of 437 non-cirrhotic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">10</span></a> There was no significant incidence of serious adverse effects &#40;AEs&#41;&#46; However&#44; the mean age of enrolled patients was 5-6 years younger in the global study than in the Japanese trial&#46; In addition&#44; these phase III trials excluded cirrhotic or non-cirrhotic patients with a history of curative treatment for HCC&#46; DAA therapy has now been approved for patients with a past history of HCC in Japan&#46; It is necessary to evaluate the preventive effects of ASV &#43; DCV therapy on the recurrence of HCC&#46;</p><p id="p0020" class="elsevierStylePara elsevierViewall">This study evaluated the anti-HCV effect and safety of ASV &#43; DCV combination therapy for compensated cir-rhotic patients compared to non-cirrhotic patients&#46; In addition&#44; the development of HCC and liver function after therapy were evaluated in cirrhotic patients&#46;</p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Material and Methods</span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Patients</span><p id="p0025" class="elsevierStylePara elsevierViewall">Before commencing treatment&#44; we checked the RAS in NS5A of 350 patients with HCV genotype 1b &#40;not shown&#41;&#46; A total of 145 patients without RAS on L31 and Y93 within the NS5A domain were enrolled for treatment with ASV &#43; DCV combination therapy&#44; consisting of 49 hepatic cir-rhotic patients and 96 non-cirrhotic patients&#46; Hepatic cirrhosis was defined as histological examination F4 or &#62; 15&#46;0 kPa according to transient elastography&#46; The enrolled patients were aged 40-86 years old and were chronically infected with HCV genotype 1b with a serum HCV RNA viral load &#62; 3 log copies&#47;mL at baseline&#46; Patients were excluded if they had medical contraindications for ASV and DCV&#44; a history of DAA use&#44; a history of drug use&#44; decom-pensated cirrhosis&#44; a Child-Pugh score &#62; 6&#44; or evidence of other significant liver diseases&#44; including hepatitis B virus&#44; autoimmune liver diseases&#44; alcoholic liver disease&#44; and viable HCC&#46; None of the patients showed evidence of infection by human immunodeficiency virus &#40;HIV&#41;&#46; This study was performed in accordance with the 1975 Declaration of Helsinki &#40;2004 version&#41;&#44; and written informed consent was obtained from all patients prior to treatment&#46; The study protocol was approved by the Ethics Committee of each hospital and by the Ethics Committee of Osaka City University Graduate School of Medicine &#40;No&#46; 2905&#41;&#46; The trial was registered in UMIN &#40;No&#46; 000015806&#41;&#46;</p></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Study design</span><p id="p0030" class="elsevierStylePara elsevierViewall">The patients were treated with 100 mg ASV &#40;Sun-vepra&#174;&#44; Bristol-Myers Squibb&#44; Tokyo&#44; Japan&#41; twice per day plus 60 mg DCV &#40;Daklinza&#174;&#44; Bristol-Myers Squibb&#41; once daily for 24 weeks&#46; A total of 110 &#40;76&#37;&#41; of the 145 patients were admitted to the hospital for 3-7 days at initiation and were educated regarding DAA therapy by a hospital pharmacist&#46; A serum liver function test and an imaging test were performed regularly for 1 year from the end of treatment &#40;EOT&#41;&#44; in addition to the evaluation of serum HCV viral load&#46;</p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Virological evaluations</span><p id="p0035" class="elsevierStylePara elsevierViewall">HCV-RNA was determined by TaqMan HCV assay &#40;COBAS&#174; TaqMan&#174; HCV assay&#44; Roche Molecular Diagnostics&#44; Tokyo&#44; Japan&#41; with a lower limit of quantification of 15 IU&#47;mL and an upper limit of quantification of 6&#46;9 x 10<span class="elsevierStyleSup">7</span> IU&#47;mL &#40;1&#46;2-7&#46;8 log IU&#47;mL&#41;&#46; The HCV genotype was determined using an HCV genotype primer kit &#40;Institute of Immunology Co&#46;&#44; Ltd&#46;&#44; Tokyo&#44; Japan&#41;&#46; RAS in the NS3&#47;4A protease and the NS5A were evaluated using the direct sequencing method according to a previously reported protocol&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">11</span></a> Resistance analysis focused on amino acid polymorphisms Q80&#44; R155&#44; A156&#44; D168&#44; and V170 within NS3&#47;4 A and of L28&#44; R30&#44; L31&#44; Q54&#44; P58&#44; Q62&#44; A92&#44; and Y93 within the NS5A domain&#46;</p><p id="p0040" class="elsevierStylePara elsevierViewall">Virological response to the therapy was defined as follows&#58; relapse showing undetectable HCV-RNA at EOT but detectable HCV RNA after EOT and re-elevation of HCV RNA at any time during treatment after a virological response &#40;breakthrough&#41;&#46; Patients in whom HCV-RNA remained stable during treatment were defined as non-responders&#46;</p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">Evaluations</span><p id="p0045" class="elsevierStylePara elsevierViewall">The rate of SVR24&#44; defined as undetectable HCV-RNA at 24 weeks after completion of treatment&#44; was used to evaluate primary efficacy&#46; In addition&#44; the improvement of liver function and HCC development were used as secondary evaluations after treatment&#46; During the follow-up period&#44; clinical&#44; biochemical&#44; and quantitative serum HCV-RNA assessments were evaluated at 1- to 3-month intervals&#46; Safety evaluations included adverse event reporting&#44; laboratory test values&#44; and physical examinations&#46; All methods used for assessing treatment efficacy were defined according to previously published guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">12</span></a></p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">SNP genotyping</span><p id="p0050" class="elsevierStylePara elsevierViewall">We examined genetic polymorphisms in the <span class="elsevierStyleItalic">interleukin 28B &#40;IL28B&#41;</span> gene in patients that consented to genetic anal-ysis&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">13</span></a> Whole blood was collected from patients and centri-fuged to separate the buffy coat&#46; Genomic DNA was extracted from the buffy coat using a QIAamp&#174; DNA Blood Midi Kit &#40;Qiagen&#44; Maryland&#44; Germantown&#44; MD&#41;&#46; Genetic polymorphisms in <span class="elsevierStyleItalic">IL28B</span> rs8099917 and rs12979860 were genotyped by TaqMan SNP Genotyping Assay with the 7500 Fast Real-Time PCR System &#40;Applied Biosystems&#44; Foster City&#44; CA&#41;&#46; All samples were also subjected to direct sequencing to confirm the genotype&#46; The primers and procedures used were as described previously&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">13&#44;14</span></a></p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Statistical analysis</span><p id="p0055" class="elsevierStylePara elsevierViewall">Data analyses were conducted using JMP software &#40;ver&#46; 9&#46;0&#59; SAS Institute&#44; Cary&#44; NC&#41;&#46; Differences between groups were evaluated by Wilcoxon&#39;s two-sample test for numerical variables or Fisher&#39;s exact test for categorical variables&#46; Variables with p &#60; 0&#46;1 in univariate analyses were subjected to stepwise multivariate logistic regression analyses&#46; In the two-tailed test&#44; p &#60; 0&#46;05 was taken to indicate statistical significance&#46;</p></span></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">RESULTS</span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Patients at baseline</span><p id="p0060" class="elsevierStylePara elsevierViewall">The clinical background of 49 hepatic cirrhotic and 96 non-cirrhotic patients are shown in <a class="elsevierStyleCrossRef" href="#t0010">table 1</a>&#46; The cirrhotic group contained 21 females and 28 males&#44; and the non-cir-rhotic group had 41 females and 54 males &#40;p &#61; 0&#46;79&#41;&#46; The median age was 71 years old &#40;range&#58; 48-86 years old&#41; in the cirrhotic group&#44; and 71 years old &#40;range&#58; 40-84 years old&#41; in the non-cirrhotic group &#40;p &#61; 0&#46;74&#41;&#46; Previous IFN-based therapies were performed in 30 patients &#40;61&#37;&#41; in the cirrhotic group and 49 &#40;51&#37;&#41; in the non-cirrhotic group&#46; The cirrhotic group had 14 &#40;29&#37;&#41; patients with curative treatment for HCC&#44; whereas the non-cirrhotic group had 8 &#40;8&#37;&#41; patients with curative treatment for HCC &#40;p &#60; 0&#46;02&#41;&#46; There were significant differences in WBC&#44; hemoglobin&#44; platelet counts&#44; and AFP levels at baseline between the cirrhotic and non-cirrhotic groups&#46; The mean HCV-RNA level was 6&#46;1 &#177; 0&#46;5 log copies&#47;mL in the cirrhotic group and 6&#46;1 &#177; 0&#46;8 log copies&#47;mL in the non-cirrhotic group &#40;p &#61; 0&#46;31&#41;&#46; RASs in the HCV NS3&#47;4A gene were detected in 15 &#40;31&#37;&#41; of 49 patients in the cirrhotic group&#58; Q80L&#44; 2&#44; D168E&#44; 3&#44; and V170I&#44; 15&#46; RASs were detected in 33 &#40;34&#37;&#41; of 96 patients in the non-cirrhotic group&#58; Q80L&#44; 4&#44; Q80R&#44; 2&#44; R155K&#44; 1&#44; D168E&#44; 2&#44; and V170I&#44; 30&#46; No differences in the distribution of the <span class="elsevierStyleItalic">IL28B</span> genotypes were detected between the two groups&#46;</p><elsevierMultimedia ident="t0010"></elsevierMultimedia></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Treatment responses in the cirrhotic and non-cirrhotic groups</span><p id="p0065" class="elsevierStylePara elsevierViewall">RVR rates were 79&#37; &#40;38&#47;48&#41; in the cirrhotic group and 86&#37; &#40;78&#47;91&#41; in the non-cirrhotic group &#40;p &#61; 0&#46;45&#41;&#46; The rates at the EOT were 98&#37; &#40;48&#47;49&#41; in the cirrhotic group and 98&#37; &#40;94&#47;96&#41; in the non-cirrhotic group &#40;p &#61; 0&#46;55&#41;&#46; The SVR24 rates were 96&#37; &#40;47&#47;49&#41; in the cirrhotic group and 96&#37; &#40;91&#47;95&#41; in the non-cirrhotic group &#40;p &#61; 0&#46;69&#41;&#46; There were no significant differences in the treatment response rate between the two groups &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 1</a>&#41;&#46; Viral breakthrough occurred in one patient in the cirrhotic group and two patients in the non-cirrhotic group &#40;p &#61; 0&#46;55&#41;&#46; At baseline RASs at D168E and V170I in the HCV NS3&#47;4A were detected in two &#40;31&#37;&#41; of three patients with viral breakthrough&#46; Viral relapse occurred in one patient in the cirrhotic group and two patients in the non-cirrhot-ic group &#40;p &#61; 0&#46;55&#41;&#46; In three patients with relapse&#44; ASV &#43; DCV therapy was stopped due to adverse effects&#46; At baseline RASs in the HCV NS3&#47;4A were not detected in all of patients with viral relapse&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0095">Adverse events and treatment discontinuation</span><p id="p0070" class="elsevierStylePara elsevierViewall">Treatment was discontinued for various reasons in the cirrhotic group&#44; as follows &#40;one patient each&#41;&#58; ALT elevation&#44; hepatic coma&#44; institutional pneumonia&#44; severe bronchitis&#44; and HCC development&#46; In the non-cirrhotic group&#44; treatment was discontinued due to ALT elevation in five patients&#44; prothrombin time elongation in two patients&#44; trauma in one patient&#44; and self-discontinuation in one patient&#46;</p><p id="p0075" class="elsevierStylePara elsevierViewall">Grade III&#47;IV adverse events occurred more frequently in the cirrhotic group &#40;10&#47;49&#59; 20&#46;4&#37;&#41; than in the non-cir-rhotic group &#40;10&#47;96&#59; 10&#46;4&#37;&#41; &#40;p &#61; 0&#46;099&#41;&#46; ALT elevation is an AE of DCV&#47;ASV therapy&#44; particularly in Japanese patients&#46; The ALT level was elevated by more than twice the normal upper limit in 9 of 49 cirrhotic patients and 19 of 96 non-cirrhotic patients&#46; There were no differences in the incidence of ALT elevation between the two groups &#40;<a class="elsevierStyleCrossRef" href="#t0015">Table 2</a>&#41;&#46; DAA therapy was stopped in one cirrhotic patient and five non-cirrhotic patients due to ALT elevation &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure 2</a>&#41;&#46; One non-cirrhotic patient died after ASV &#43; DCV therapy due to events that were not related to the treatment&#46;</p><elsevierMultimedia ident="t0015"></elsevierMultimedia><elsevierMultimedia ident="f0015"></elsevierMultimedia></span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0100">Prognosis of liver function and development of HCC after therapy in cirrhotic patients</span><p id="p0080" class="elsevierStylePara elsevierViewall">First&#44; liver biochemical markers were evaluated in 47 cirrhotic patients that achieved SVR&#46; Compared to the baseline&#44; ALT and AFP levels were significantly decreased at EOT&#44; post-24th week&#44; and post-48th week &#40;p &#60; 0&#46;01&#41;&#46; In addition&#44; albumin levels were gradually increased after ASV &#43; DCV therapy &#40;<a class="elsevierStyleCrossRef" href="#f0020">Figure 3</a>&#41;&#46;</p><elsevierMultimedia ident="f0020"></elsevierMultimedia><p id="p0085" class="elsevierStylePara elsevierViewall">In all&#44; 22 patients had received curative treatment for HCC before ASV &#43; DCV therapy&#46; After confirming the lack of HCC recurrence by contrast computed tomography or magnetic resonance imaging&#44; ASV &#43; DCV therapy was started&#46; Over 48 weeks from the end of anti-HCV therapy&#44; recurrence of HCC was observed in 6 &#40;43&#37;&#41; of 14 cirrhotic&#44; and 1 &#40;12&#46;5&#37;&#41; of 8 non-cirrhotic patients&#46; On the other hand&#44; HCC developed in 2 &#40;5&#46;7&#37;&#41; of 35 cirrhot-ic&#44; and 1 &#40;1&#46;2&#37;&#41; of 88 non-cirrhotic patients &#40;<a class="elsevierStyleCrossRef" href="#f0025">Figure 4</a>&#41;&#46; HCC recurrence and occurrence were observed more frequently in the cirrhotic group than in the non-cirrhotic group&#46;</p><elsevierMultimedia ident="f0025"></elsevierMultimedia></span></span><span id="s0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0105">Discussion</span><p id="p0090" class="elsevierStylePara elsevierViewall">In the present study&#44; 96&#37; of cirrhotic and non-cirrhotic patients without RAS in NS5A achieved SVR after ASV &#43; DCV therapy&#46; RAS-oriented ASV &#43; DCV therapy was also reasonable for HCV genotype 1b patients with cirrhosis&#46; Previous reports have indicated SVR rates of 88&#46;3-93&#46;7&#37; in patients without RAS in NS5A&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">15-17</span></a> The anti-viral effect observed in our study was slightly higher than those results&#46; In our study&#44; 76&#37; patients started treatment at admission&#44; and were instructed regarding DAA by a hospital pharmacist&#46; Only 2 &#40;1&#46;7&#37;&#41; of 115 patients did not achieve SVR in the admitted group&#44; and 4 &#40;11&#37;&#41; of 35 patients without admission failed to achieve SVR &#40;p &#61; 0&#46;039&#41;&#46; These results suggest that admission with commencement of DAA be recommended&#44; particularly in Japan&#46;</p><p id="p0095" class="elsevierStylePara elsevierViewall">On the other hand&#44; AEs &#40;adverse events&#41; of grade III&#47;IV occurred more frequently in cirrhotic patients than in non-cirrhotic patients during treatment&#46; Elevation of ALT was a unique AE associated with ASV &#43; DCV therapy&#46; There were no differences in the incidence of serious ALT elevation between cirrhotic and non-cirrhotic groups&#46; Bleeding in the digestive tract and hepatic coma were serious AEs seen only in the cirrhotic group&#46; Compared to the Japanese phase III trial&#44; there were some differences in AEs in the present study&#46; These differences may have been due to the characteristics of the enrolled patients in terms of their age&#44; gender&#44; cirrhosis status&#44; and history of HCC&#46; Taken together&#44; these results suggest that careful management is necessary for cirrhotic patients before and during ASV &#43; DCV therapy&#46;</p><p id="p0100" class="elsevierStylePara elsevierViewall">A follow-up study showed that ALT levels and AFP levels decreased significantly after EOT in cirrhotic patients that achieved SVR&#46; In addition&#44; serum levels of albumin and platelet count significantly increased compared to baseline measurements&#46; Our data are consistent with previous reports&#46; Miyaki&#44; <span class="elsevierStyleItalic">et al</span>&#46; showed that serum fibrosis markers are improved in SVR patients&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">18</span></a> Mandorfer&#44; <span class="elsevierStyleItalic">et al</span>&#46; reported that DAA therapy decreases portal pressure in SVR patients with moderate hepatic fibrosis as determined by measuring hepatic venous pressure gradient&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">19</span></a> These data suggest that the elimination of HCV by DAA therapy improved liver function in cirrhotic patients&#46;</p><p id="p0105" class="elsevierStylePara elsevierViewall">On the other hand&#44; the incidence rates of HCC development and recurrence were higher in cirrhotic patients&#46; Conti&#44; <span class="elsevierStyleItalic">et al</span>&#46; reported that HCC was detected during 24-weeks of follow-up in 17 &#40;29&#37;&#41; of 59 patients with previous HCC and 9 &#40;3&#37;&#41; of 285 cirrhotic patients without HCC&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">20</span></a> Our observations are in line with those of other previous studies&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">21</span></a> Both the observation period and the incidence of HCC in our study were double those in these previous studies&#46; Previous Japanese studies of IFN-based therapy showed that age and fibrosis at baseline were closely related to HCC development in SVR patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">3&#44;22</span></a> Although the reasons for the high incidence of HCC development in patients treated with DAA are not clear&#44; greater age and more-advanced fibrosis might be related to the development of HCC&#46;</p><p id="p0110" class="elsevierStylePara elsevierViewall">IFN-based therapy without DAA showed a preventive effect on the development of HCC in patients with HCV&#44; even in those who did not achieve SVR&#46; It was speculated that IFN had two effects&#44; i&#46;e&#46;&#44; antivirus and antitumor effects&#46; On the other hand&#44; DAAs were designed as specific inhibitors of HCV and did not have direct antitumor sup-pressive effects&#46; Minami&#44; <span class="elsevierStyleItalic">et al</span>&#46; compared the rate of HCC development between a DAA treatment group&#44; an IFN-based therapy group&#44; and a control group&#46; The rate of early recurrence was not different between the three groups&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">23</span></a> It is important to monitor cirrhotic patients that achieve SVR with DAA therapy&#46;</p><p id="p0115" class="elsevierStylePara elsevierViewall">The present study had several limitations&#46; First&#44; the number of patients enrolled in the study was low&#44; although the number was greater than in the phase III clinical trial&#46; In September 2015&#44; a 12-week IFN-free regimen was approved for HCV genotype 1 in Japan&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">24&#44;25</span></a> It is difficult to implement a study in a larger cohort because patients prefer therapies with shorter durations&#46; Second&#44; there were no decompensated cirrhotic patients in the present study&#44; as anti-HCV therapy is not approved for such patients in Japan&#46; Finally&#44; the follow-up period was insufficient to evaluate prognoses in cirrhotic patients with SVR&#46; SVR is an important process but is not the goal of treatment in cases of chronic viral liver disease&#46; It is necessary to evaluate long-term prognoses in cirrhotic patients with HCV&#44; including the prevention of HCC development and the prevention of hepatic failure&#46;</p><p id="p0120" class="elsevierStylePara elsevierViewall">Taken together&#44; our findings suggest that ASV &#43; DCV therapy can achieve a high SVR rate in Japanese cirrhotic patients with NS5A wild-type HCV genotype 1b and also improve liver function&#44; including albumin and AFP levels&#46; However&#44; AEs occur frequently in cirrhotic patients&#44; particularly the recurrence and occurrence of HCC after therapy&#46;</p></span><span id="s0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0110">Acknowledgments</span><p id="p0125" class="elsevierStylePara elsevierViewall">This study was supported in a part by Japan Society for the Promotion of Science grant 15k09019 &#40;AT&#41;&#46; We would like to thank Ms&#46; Yoko Yasuhara&#44; Ms&#46; Tomoko Hirano and Ms&#46; Sanae Deguchi for collecting the data&#46;</p></span><span id="s0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0115">Abbreviations</span><p id="p0130" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">&#8226;</span><p id="p0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">AEs&#58;</span> adverse events&#46;</p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">&#8226;</span><p id="p0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ALT&#58;</span> alanine aminotransferase&#46;</p></li><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">&#8226;</span><p id="p0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">EOTR&#58;</span> end of treatment response&#46;</p></li><li class="elsevierStyleListItem" id="u0025"><span class="elsevierStyleLabel">&#8226;</span><p id="p0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCC&#58;</span> hepatocellular carcinoma&#46;</p></li><li class="elsevierStyleListItem" id="u0030"><span class="elsevierStyleLabel">&#8226;</span><p id="p0155" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCV&#58;</span> hepatitis C virus&#46;</p></li><li class="elsevierStyleListItem" id="u0035"><span class="elsevierStyleLabel">&#8226;</span><p id="p0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">IL28B&#58;</span> interleukin 28 B&#46;</p></li><li class="elsevierStyleListItem" id="u0040"><span class="elsevierStyleLabel">&#8226;</span><p id="p0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">RAS&#58;</span> resistance-associated substitution&#46;</p></li><li class="elsevierStyleListItem" id="u0045"><span class="elsevierStyleLabel">&#8226;</span><p id="p0170" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">RVR&#58;</span> rapid virological responders&#46;</p></li><li class="elsevierStyleListItem" id="u0050"><span class="elsevierStyleLabel">&#8226;</span><p id="p0175" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SVR&#58;</span> sustained viral response&#46;</p></li><li class="elsevierStyleListItem" id="u0055"><span class="elsevierStyleLabel">&#8226;</span><p id="p0180" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">UNL&#58;</span> upper normal limit&#46;</p></li></ul></p></span><span id="s0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0120">Conflicts of Interest</span><p id="p0185" class="elsevierStylePara elsevierViewall">All authors declare that we have nothing to disclose regarding funding or conflict of interest with respect to the study reported in this manuscript&#46;</p></span></span>"
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          "titulo" => "Abstract"
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              "identificador" => "abs0010"
              "titulo" => "Background"
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          "identificador" => "xpalclavsec1116238"
          "titulo" => "Keywords"
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        2 => array:2 [
          "identificador" => "s0010"
          "titulo" => "Introduction"
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          "titulo" => "Material and Methods"
          "secciones" => array:6 [
            0 => array:2 [
              "identificador" => "s0020"
              "titulo" => "Patients"
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            1 => array:2 [
              "identificador" => "s0025"
              "titulo" => "Study design"
            ]
            2 => array:2 [
              "identificador" => "s0030"
              "titulo" => "Virological evaluations"
            ]
            3 => array:2 [
              "identificador" => "s0035"
              "titulo" => "Evaluations"
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            4 => array:2 [
              "identificador" => "s0040"
              "titulo" => "SNP genotyping"
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            5 => array:2 [
              "identificador" => "s0045"
              "titulo" => "Statistical analysis"
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        ]
        4 => array:3 [
          "identificador" => "s0050"
          "titulo" => "RESULTS"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "s0055"
              "titulo" => "Patients at baseline"
            ]
            1 => array:2 [
              "identificador" => "s0060"
              "titulo" => "Treatment responses in the cirrhotic and non-cirrhotic groups"
            ]
            2 => array:2 [
              "identificador" => "s0065"
              "titulo" => "Adverse events and treatment discontinuation"
            ]
            3 => array:2 [
              "identificador" => "s0070"
              "titulo" => "Prognosis of liver function and development of HCC after therapy in cirrhotic patients"
            ]
          ]
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        5 => array:2 [
          "identificador" => "s0075"
          "titulo" => "Discussion"
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          "titulo" => "Acknowledgments"
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          "identificador" => "s0085"
          "titulo" => "Abbreviations"
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          "identificador" => "s0090"
          "titulo" => "Conflicts of Interest"
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        9 => array:1 [
          "titulo" => "References"
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    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2017-02-08"
    "fechaAceptado" => "2017-03-23"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1116238"
          "palabras" => array:4 [
            0 => "Adverse events"
            1 => "Hepatocellular carcinoma"
            2 => "Resistance-associated substitution"
            3 => "Sustained viral response"
          ]
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    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015"><span class="elsevierStyleBold">Background</span></span><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">The efficacy and safety of asunaprevir &#43; daclatasvir combination therapy for treatment of hepatitis C virus &#40;HCV&#41; in compensated cirrhotic patients was not fully evaluated in real-world&#46; Outcomes were assessed in cirrhotic patients with sustained viral response &#40;SVR&#41;&#46;</p></span> <span id="abs0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020"><span class="elsevierStyleBold">Material and methods</span></span><p id="sp0050" class="elsevierStyleSimplePara elsevierViewall">A total of 145 patients without resistance-associated substitutions &#40;RASs&#41; at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b&#44; consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients&#44; were enrolled to the therapy&#46; The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks&#46; The primary endpoint was SVR 24 weeks after completing treatment&#46; In addition&#44; we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment &#40;EOT&#41;&#46;</p></span> <span id="abs0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025"><span class="elsevierStyleBold">Results</span></span><p id="sp0055" class="elsevierStyleSimplePara elsevierViewall">The SVR24 rate was 96&#37; &#40;47&#47;49&#41; in the cirrhotic group and 96&#37; &#40;91&#47;95&#41; in the non-cirrhotic group &#40;p &#61; 0&#46;69&#41;&#46; During treatment&#44; grade III&#47;IV adverse events occurred more frequently in cir-rhotic patients &#40;10&#47;49&#59; 20&#46;4&#37;&#41; than in non-cirrhotic patients &#40;10&#47;96&#59; 10&#46;4&#37;&#41; &#40;p &#61; 0&#46;099&#41;&#46; After EOT&#44; alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR&#46; In addition&#44; serum levels of albumin and platelet counts were significantly increased&#46; On the other hand&#44; the rates of HCC recurrence &#40;43&#37;&#41; and development &#40;7&#46;4&#37;&#41; were higher in cirrhotic patients than in the non-cirrhotic patients &#40;12&#46;5&#37; and 1&#46;1&#37;&#44; respectively&#41;&#46;</p></span> <span id="abs0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030"><span class="elsevierStyleBold">Conclusion</span></span><p id="sp0060" class="elsevierStyleSimplePara elsevierViewall">RAS-oriented asunaprevir&#47;daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b&#46; However&#44; careful management is necessary in patients with cirrhosis&#46;</p></span>"
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            "identificador" => "abs0010"
            "titulo" => "Background"
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            "titulo" => "Material and methods"
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            "titulo" => "Results"
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            "titulo" => "Conclusion"
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        "etiqueta" => "Figure 1"
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        "figura" => array:1 [
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          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Rapid virological response &#40;RVR&#41;&#44; end-of-treatment response &#40;EOTR&#41;&#44; sustained virological response 12 weeks after completing treatment &#40;SVR12&#41;&#44; and SVR 24 weeks after completing treatment &#40;SVR24&#41; in cirrhot-ic and non-cirrhotic groups&#46; RVR rates were 79&#37; &#40;38&#47;48&#41; in the cirrhotic group and 86&#37; &#40;78&#47;91&#41; in the non-cirrhotic group&#46; EOT rates were 98&#37; &#40;48&#47; 49&#41; in the cirrhotic group and 98&#37; &#40;94&#47;96&#41; in the non-cirrhotic group&#46; SVR12 and SVR24 rates were 96&#37; &#40;47&#47;49&#41; and 96&#37; &#40;47&#47;49&#41; in the cirrhotic group&#44; and 97&#37; &#40;92&#47;95&#41; and 96&#37; &#40;91&#47;95&#41; in the non-cirrhotic group&#44; respectively&#46; The rates at all-time points were not significantly different between the cir-rhotic and non-cirrhotic groups&#46;</p>"
        ]
      ]
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        "etiqueta" => "Figure 2"
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Change from baseline ALT levels during ASV &#43; DCV treatment in cirrhot-ic and non-cirrhotic groups&#46; &#42; Treatment was stopped due to ALT elevation&#46;</p>"
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      ]
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        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
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          "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Changes in ALT&#44; AFP&#44; and serum levels of albumin and platelet count in cirrhotic patients that achieved SVR due to ASV &#43; DCV therapy&#46; Compared to baseline&#44; ALT and AFP levels were significantly decreased after treatment&#46; Albumin levels and platelet count were increased&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "f0025"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "figura" => array:1 [
          0 => array:4 [
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          "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">HCC recurrence and development during 1-year follow-up from the end of treatment&#46; HCC recurred in 6 &#40;43&#37;&#41; of 14 cirrhotic and 1 &#40;12&#46;5&#37;&#41; of 8 non-cirrhotic patients that had previous curative HCC therapy&#46; HCC developed in 2 &#40;7&#46;4&#37;&#41; of 27 cirrhotic and 1 &#40;1&#37;&#41; of 96 non-cirrhotic patients&#46;</p>"
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          "leyenda" => "<p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">IFN&#58; interferon&#46; HCC&#58; hepatocellular carcinoma&#46; RFA&#58; radiofrequency ablation&#46; TACE&#58; trans-catheter arterial chemoembolization&#46; RAVs&#58; resistant associated variants&#46; WBC&#58; white blood cell&#46; Hb&#58; hemoglobin&#46; Plt&#58; platelet&#46; ALT&#58; alanine aminotransferase&#46; &#947;-GTP&#58; gamma-glutamyl transpeptidase&#46; AFP&#58; alpha protein&#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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cirrhotic group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-cirrhotic group&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Number of patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Male&#47;female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">21&#47;28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&#47;54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Median age &#40;range&#41; years old&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">71 &#40;48-86&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71 &#40;40-84&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Body weight &#40;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">54&#46;7 &#40;40-95&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">55&#46;8 &#40;38&#46;1-94&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Previous IFN therapy &#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#47;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#47;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Curative treatment of HCC &#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&#47;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#47;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Operation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RFA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TACE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">IL28B</span> genotype &#40;major&#47;non-major&#47;NT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#47;15&#47;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&#47;36&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HCV RNA &#40;log copies&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;9 &#40;3&#46;6-7&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46;8 &#40;3&#46;4-7&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS3&#47;4A RAS &#40;&#177;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Q80 &#40;wild&#47;L&#47;R&#41; D168 &#40;wild&#47;E&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">47&#47;2&#47;0 46&#47;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">90&#47;4&#47;2 94&#47;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;3 0&#46;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">WBC &#40;&#47;&#956;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#44;900 &#40;1&#44;600-8&#44;800&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5000 &#40;2&#44;300-10&#44;400&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hb &#40;g&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&#46;9 &#40;8&#46;3-16&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&#46;6 &#40;9&#46;8-16&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Plt &#40;x10<span class="elsevierStyleSup">4</span>&#47;&#956;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;7 &#40;3&#46;7-20&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#46;4 &#40;7&#46;1-29&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T&#46; Bil &#40;mg&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;8 &#40;0&#46;3-2&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;7 &#40;0&#46;2-1&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Albumin &#40;g&#47;dL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;5 &#40;2&#46;5-4&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;9 &#40;3&#46;1-4&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALT &#40;IU&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48 &#40;15-149&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40 &#40;9-231&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#947;-GTP &#40;IU&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41 &#40;13-199&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">34 &#40;11-752&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Creatinine &#40;mg&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;7 &#40;0&#46;38-1&#46;43&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;71 &#40;0&#46;41-1&#46;83&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AFP &#40;ng&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#46;5 &#40;1-375&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;8 &#40;1-143&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60; 0&#46;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2045100.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics of patients with L31 and Y93 in NS5A of HCV genotype 1b infection in cirrhotic and non-cirrhotic groups&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "t0015"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cirrhotic &#40;n &#61; 49&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Non-cirrhotic &#40;n &#61; 96&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Discontinuation due to AEs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5 &#40;10&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;10&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;96&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serious AEs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10 &#40;10&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;099&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ALT elevation &#62; fivefold from UNL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bleeding in digestive tract&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatic coma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elongation of prothrombin time&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Renal impairment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interstitial pneumonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bronchitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fever&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HCC recurrence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diarrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Trauma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other reasons for discontinuation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Viral breakthrough&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Self-discontinuation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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Article information

ISSN: 16652681
Original language: English

DOI:10.5604/01.3001.0010.2732

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	5	0	5
2024 October	37	4	41
2024 September	20	4	24
2024 August	31	1	32
2024 July	23	0	23
2024 June	25	2	27
2024 May	23	3	26
2024 April	19	6	25
2024 March	39	5	44
2024 February	28	4	32
2024 January	22	3	25
2023 December	10	3	13
2023 November	8	2	10
2023 October	13	5	18
2023 September	10	0	10
2023 August	14	3	17
2023 July	16	6	22
2023 June	22	1	23
2023 May	55	2	57
2023 April	57	0	57
2023 March	45	3	48
2023 February	27	4	31
2023 January	36	3	39
2022 December	28	5	33
2022 November	19	9	28
2022 October	17	5	22
2022 September	14	7	21
2022 August	9	6	15
2022 July	19	9	28
2022 June	14	6	20
2022 May	7	9	16
2022 April	11	13	24
2022 March	14	7	21
2022 February	10	5	15
2022 January	20	5	25
2021 December	9	6	15
2021 November	12	8	20
2021 October	13	15	28
2021 September	14	7	21
2021 August	9	9	18
2021 July	11	7	18
2021 June	7	7	14
2021 May	23	6	29
2021 April	22	6	28
2021 March	19	8	27
2021 February	7	7	14
2021 January	8	4	12
2020 December	8	7	15
2020 November	15	5	20
2020 October	11	5	16
2020 September	12	8	20
2020 August	10	9	19
2020 July	7	10	17
2020 June	5	6	11
2020 May	8	5	13
2020 April	7	1	8
2020 March	3	4	7
2020 February	8	4	12
2020 January	11	4	15
2019 December	9	6	15
2019 November	5	2	7
2019 October	3	2	5
2019 September	6	0	6
2019 August	1	1	2
2019 July	7	9	16
2019 June	11	9	20
2019 May	2	5	7

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