Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4 in adolescents
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Lerias de Almeida, Angelo Alves de Mattos, Cristiane Valle Tovo" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Paulo R." "apellidos" => "Lerias de Almeida" ] 1 => array:2 [ "nombre" => "Angelo" "apellidos" => "Alves de Mattos" ] 2 => array:2 [ "nombre" => "Cristiane" "apellidos" => "Valle Tovo" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119316539?idApp=UINPBA00004N" "url" => "/16652681/0000000900000002/v1_201907070740/S1665268119316539/v1_201907070740/en/main.assets" ] "en" => array:16 [ "idiomaDefecto" => true "titulo" => "Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4 in adolescents" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "156" "paginaFinal" => "160" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Jaber Al Ali, Salem Owayed, Wafa’a Al-Qabandi, Khaled Husain, Fuad Hasan" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Jaber" "apellidos" => "Al Ali" "email" => array:1 [ 0 => "alalimd@hsc.edu.kw" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor1" ] ] ] 1 => array:3 [ "nombre" => "Salem" "apellidos" => "Owayed" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">***</span>" "identificador" => "aff3" ] ] ] 2 => array:3 [ "nombre" => "Wafa’a" "apellidos" => "Al-Qabandi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] 3 => array:3 [ "nombre" => "Khaled" "apellidos" => "Husain" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">**</span>" "identificador" => "aff2" ] ] ] 4 => array:3 [ "nombre" => "Fuad" "apellidos" => "Hasan" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff1" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "From the Faculty of Medicine, Kuwait University" "etiqueta" => "*" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Jabriya, Kuwait; Amiri Hospital" "etiqueta" => "**" "identificador" => "aff2" ] 2 => array:3 [ "entidad" => "Safat, Kuwait; Al Adan Hospital, Hadiya, Kuwait, Ministry of Health, Kuwait" "etiqueta" => "***" "identificador" => "aff3" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Correspondence and reprint request:" ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 564 "Ancho" => 1000 "Tamanyo" => 112287 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Response to therapy.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="p0030" class="elsevierStylePara elsevierViewall">Hepatitis C Virus (HCV) is a major cause of liver disease in the Middle East where, in some population, the prevalence rate reaches 15–20%.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In chronically infected adults, 20% develop cirrhosis and hepatocellular carcinoma. The natural history of HCV infection in children and adolescents is less certain. In a recent multi center study from Italy 504 HCV seropositive children were followed prospectively and retrospectively.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Spontaneous viral clearance was observed in only 8% of the patients, most of whom were infected with HCV genotype 3. Another concerning observation was that 1.8% of the reported children progressed to decompensated cirrhosis. Risk factors associated with progression included perinatal acquisition of the virus and co-morbid conditions such as thalassemia.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> These observations and the fact that infected children represent a reservoir for infection and may suffer from the social stigma associated with infection, have prompted a number of therapeutic trials using non-pegylated interferon alone or in combination with ribavirin.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Most of these trials were small. Similarly data regarding the efficacy and safety of pe-gylated interferon alone or plus ribavirin in children and adolescent are very limited.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Moreover, the studies were carried out in Western communities where HCV genotype 1 is the predominant variant followed by genotype 2/3 and may not generalized to the Gulf states where genotype 4 is endemic and where demographic differences may affect anti-viral response.</p><p id="p0035" class="elsevierStylePara elsevierViewall">The aim of this pilot study was to determine the efficacy and safety of pegylated interferon alfa-2b plus weight based ribavirin combination therapy in adolescents infected with HCV genotype 4.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Patients and Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Patients selection</span><p id="p0040" class="elsevierStylePara elsevierViewall">Treatment-naive patients, aged 14 to 17 years, with detectable HCV RNA, genotype 4 and anti-HCV positive liver biopsy findings consistent with the diagnosis of chronic hepatitis C were eligible for study participation. The patients were seen by their physicians and the decision to treat was a decision made by both physician and patient/patient’s family on clinical grounds. They study included only those patients for whom a decision to treat was made. The patients were excluded if there was clinical or biochemical evidence of hepatic decompensation, severe psychiatric disorders, hemoglobin < 100 g/L, white blood cell count < 2,500/mm<span class="elsevierStyleSup">3</span>, platelet counts <70,000/mm<span class="elsevierStyleSup">3</span>, and serum creatinine level > 200 mmol/L. Informed consent was obtained from all patients and their parents prior to study enrollment in accordance with the ethical code of our institution. This study was approved by our institutional ethical review board.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Study design and efficacy end points</span><p id="p0045" class="elsevierStylePara elsevierViewall">Twelve children and adolescents (8 males) with chronic HCV were included in an open-label uncontrolled pilot study (<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>). The patients were included independent of mode of acquisition of infection, level of serum aminotransaminases, or serum HCV RNA viral load. All patients received subcutaneous peginterferon alfa-2b at a dose of 1.5 μg/kg body weight once per week plus rebavi-rin (15 mg/kg/day) (Pegatron, Schering-Plough Inc) for 48 weeks. The primary efficacy end point was sustained virological response (SVR), defined as an undetectable (< 50 IU/mL) HCV RNA after 24 weeks of treatment-free follow-up (week 72), Secondary end points include early virologic response (EVR), defined as HCV RNA < 50 IU/mL at week 12 of therapy, and end-of-treatment response (ETR), defined as HCV RNA < 50 IU/Ml at week 48.</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0050" class="elsevierStylePara elsevierViewall">Serum HCV RNA testing was performed using a qualitative polymerase chain reaction assay (COBAS AMPLICOR HCV TEST V 2.0, Roche Diagnostics) A liver biopsy was performed on all patients pre-treatment and the METAVIR scoring system was used to grade liver histology. All mothers were tested for anti-HCV antibodies.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Safety assessments</span><p id="p0055" class="elsevierStylePara elsevierViewall">The clinical and laboratory data as well as adverse effects were evaluated and reviewed, with the completion of case report forms, at weeks 1, 2, 4, 6, 8, and 12 and monthly thereafter, Stepwise reductions in peginterferon alfa-2b or ribavirin dose were permitted for management of adverse events and laboratory abnormalities. Hematologic growth factors were allowed when indicated, for clinically significant anemia or neutropenia at the discretion of the study investigators.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Compliance monitoring</span><p id="p0060" class="elsevierStylePara elsevierViewall">In all patients, peginterferon alfa-2b was administered in the local primary care clinic by a registered nurse who documented compliance. Adherence to ri-bavirin ingestion was monitored by capsule count.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="p0065" class="elsevierStylePara elsevierViewall">Of 12 children and adolescents (<a class="elsevierStyleCrossRef" href="#t0005">Table 1</a>), 11 completed the study. On pre-treatment liver biopsy, all patients had histology features of active hepatitis without cirrhosis, Mean age at diagnoses was 15.75 years (range 14–17 years), the alanine aminotransferase (ALT) values were abnormal in 10 patients (83%), with a mean of 91 IU/L (range: 34–194 IU/L). HCV RNA was detected in the baseline sera of all patients with a median level of 0.78 x 10<span class="elsevierStyleSup">6</span> IU/ml (range: 0.23-1.8 x 10<span class="elsevierStyleSup">6</span>) One patient withdrew from study after 4 months because of the development of type 1 diabetes mellitus. All remaining patients took at least 80% of the peginterferon alfa-2b and ribavi-rin. Early virologic response (EVR) and end-of-treat-ment response (ETR) were achieved in 10 (83%) of 12 patients, and sustained virologic response was achieved in 9 (75%) of 12 patients (<a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a>). All patients who achieved an SVR also achieved an EVR. Two patients were nonresponders, one patient achieved an ETR and then relapsed during the third month of follow up. The two nonresponders had baseline HCV RNA levels that were higher than those of most other patients (1.1 x 10<span class="elsevierStyleSup">6</span> IU/ML and 1.8 x 10<span class="elsevierStyleSup">6</span> IU/ML).</p><elsevierMultimedia ident="t0005"></elsevierMultimedia><elsevierMultimedia ident="f0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Route of acquisition of infection</span><p id="p0070" class="elsevierStylePara elsevierViewall">Of 12 patients, 2 (17%) had extensive dental procedures, 2 (17%) gave history of parenteral drug use, 2 (17%) were born to mothers infected with HCV raising the suspicion of vertical transmission, and 1 (8%) had multiple blood transfusions. The rest (42%) did not have an identifiable risk factor for HCV.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Adverse effects of treatment</span><p id="p0075" class="elsevierStylePara elsevierViewall">Flu-like symptoms were the most common adverse event and all patients experienced fever (<a class="elsevierStyleCrossRef" href="#t0010">Table 2</a>). Sixty-seven percent of the patients had leucopenia, but only 1 patient required treatment with growth factors. Anemia developed in 4 patients, 3 of them were females. They all had coincidental menorrha-gia. The dose of ribavirin of these patients was reduced when hemoglobin was below 10 gm/dL.</p><elsevierMultimedia ident="t0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Discussion</span><p id="p0080" class="elsevierStylePara elsevierViewall">The combination of pegylated interferon alfa and ribavirin is currently the standard therapy for chronic hepatitis C infection in adults. Sustained virolo-gic response is achieved in 44–75% of patients depending on genotype.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The single most important determinant of treatment response is viral genotype, such that 45–50% of patients infected with HCV genotype 1 experience an SVR compared to 75% of those infected with genotypes 2 and 3. Data regarding the efficiency of pegylated interferon plus ribavirin combination therapy in genotype 4 infected patients are limited because most of the large registration trials were conducted in western countries where HCV genotype 4 is relatively uncommon and some trials may have excluded genotype 4. In the Middle East, however, most HCV infections are caused by the genotype 4 variant. Pegylated interferon plus ribivarin therapy has been reported to be associated with a SVR of 68% in adults infected with this genotype.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">In children and adolescents infected with HCV data regarding antiviral therapy are very limited and almost non-existent for genotype 4 patients. Standard non-pegylated interferon monotherapy was associated with an SVR in 33–45% of patients.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> With the use of standard non-pegylated interferon plus ribavirin combination in children and adolescents. The SVR rate varied from 41–61%<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>,<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleSup">-</span><a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> depending on HCV genotype.</p><p id="p0090" class="elsevierStylePara elsevierViewall">With regards to the current gold-standard therapy of peginterferon and ribavirin which has only recently recently approved by United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) for a healthy children over three years of age,<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> there are only a few published reports regarding its efficacy and safety in children and adolescent with chronic hepatitis C. In an open-labeled uncontrolled trial from Germany 62 children and adolescents were treated with peginterferon alfa-2b and ribavirin for 48 weeks.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The overall SVR was 58%.</p><p id="p0095" class="elsevierStylePara elsevierViewall">The mode of transmission appeared to influence treatment outcome. SVR was achieved in 70% and 48% of patients who acquired HCV through parente-ral exposure, or by vertical transmission respectively. But, as in adults, HCV genotype was the main determinant of response. The rate of SVR among patients with genotype 1 was 47%, compared to 100% in patients infected with genotypes 2 and 3. The study included only 2 children with genotype 4, one of whom had a SVR. However, in a recent global, mul-ticenter, open-label study, where 107 children and adolescents enrolled and treated with combination therapy, the overall SVR was achieved by 65% of all patients, genotype was the main predictor of response with 53%, 93 and 80% in patients infected with G1, G2/3 and G4, respectively.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> To date we could not find published reports regarding the efficacy and safety of pegylated interferon and ribavirin in adolescents infected with HCV genotype 4. The SVR, in our study, was comparable to what we had observed in adults.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">,</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In our study it is important to note that nine patients with EVR had SVR and more importantly that the two patients without EVR had no SVR. The small number of patients included in this study limits the analyses but this data suggests that stopping therapy in those without response after 12 weeks of treatment is appropriate for HCV type 4. A number of factors might have contributed to the relatively high response rate. Most patients had mild liver disease, but most importantly low pre-treat-ment viral load. Furthermore, compliance was excellent, because patients and parents were counseled extensively, more importantly compared to the western culture, Arab adolescents comply with family traditions for abiding to their parents’ wishes. A relatively high dose of ribavirin (15 mg/kg) was used. The latter has been shown to induce better SVR.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The cause for extending therapy for 48 weeks is that the value of early virologic response as a predictor of SVR was not well established in children. Moreover, at the time, there was evidence in adults that non-responders may benefit from interferon therapy in terms of histologic activity. Also, per protocol, we wanted the entire group to receive the same drug regimen for uniformity. Finally, most of our patients had presumed parenterally acquired disease.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusion</span><p id="p0100" class="elsevierStylePara elsevierViewall">This small open label pilot study shows that pe-gylated interferon plus ribavirin appear to be effective and relatively safe for the treatment of HCV genotype 4 in adolescent and children. Treating this population, therefore, may be appropriate. However, larger controlled trials are needed to confirm our findings.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Abreviations</span><p id="p0105" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="li0005"><li class="elsevierStyleListItem" id="list0005"><span class="elsevierStyleLabel">•</span><p id="p0110" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCV:</span> Hepatitis C virus.</p></li><li class="elsevierStyleListItem" id="list0010"><span class="elsevierStyleLabel">•</span><p id="p0115" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Anti-HCV:</span> Antibody to hepatitis C virus.</p></li><li class="elsevierStyleListItem" id="list0015"><span class="elsevierStyleLabel">•</span><p id="p0120" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ALT:</span> Alanine aminotransferase.</p></li><li class="elsevierStyleListItem" id="list0020"><span class="elsevierStyleLabel">•</span><p id="p0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SVR:</span> Sustained virological response.</p></li><li class="elsevierStyleListItem" id="list0025"><span class="elsevierStyleLabel">•</span><p id="p0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">EVR:</span> Early virological response.</p></li><li class="elsevierStyleListItem" id="list0030"><span class="elsevierStyleLabel">•</span><p id="p0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ETR:</span> End-of-treatment response.</p></li><li class="elsevierStyleListItem" id="list0035"><span class="elsevierStyleLabel">•</span><p id="p0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">IVDU:</span> Intravenous drug user.</p></li><li class="elsevierStyleListItem" id="list0040"><span class="elsevierStyleLabel">•</span><p id="p0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCV RNA:</span> Hepatitis C ribonucleic acid.</p></li></ul></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Grants and Financial Support</span><p id="p0150" class="elsevierStylePara elsevierViewall">This is original work and I wish this work to be published under the section of original paper.</p><p id="p0155" class="elsevierStylePara elsevierViewall">No financial support has been availed from anyone.</p></span></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:3 [ "identificador" => "xres1217528" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abs0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1132909" "titulo" => "Key words" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Patients and Methods" "secciones" => array:11 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients selection" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Study design and efficacy end points" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Safety assessments" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Compliance monitoring" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Results" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Route of acquisition of infection" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Adverse effects of treatment" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Abreviations" ] 10 => array:2 [ "identificador" => "sec0065" "titulo" => "Grants and Financial Support" ] ] ] 4 => array:1 [ "titulo" => "Reference" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Key words" "identificador" => "xpalclavsec1132909" "palabras" => array:4 [ 0 => "Chronic hepatitis C virus" 1 => "Genotype 4" 2 => "Adolescents" 3 => "Peginterferon alpha-2b" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abs0005" class="elsevierStyleSection elsevierViewall"><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Background.</span> Hepatitis C is endemic in the Middle East where genotype R accounts for most cases. Data regarding the safety and efficacy of peginterferon plus ribavirin for the treatment of chronic hepatitis C in children and adolescents, particularly those infected with genotype R is limited.</p><p id="sp1025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Aim.</span> To evaluate the efficacy and tolerability of peginterferon alfa-2b in combination with ribavirin in adolescents chronically infected with HCV genotype R.</p><p id="sp2025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Patients and methods.</span> In an open-labeled, uncontrolled pilot study, 12 adolescents (rangeIR-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 mg/ kg body weight once per week plus oral ribavirin (15 mg/kg/day) for R8 weeks. Patients were followed for 2R weeks post-treatment. All patients had biopsy proven hepatitis without cirrhosis.</p><p id="sp3025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Results.</span> One patient withdrew from the study due to developing insulin dependent diabetes mellitus R months into treatment. The remaining patients received at least 80% of the prescribed dose of pegylated interferon and ribavirin. Sustained viral response was observed in 9 patients (75%). The most frequent side effect was flu like illness which was reported in all patients. Sixty seven percent had leucopenia, but only one individual required adjuvant therapy with hematologic growth factor. Four patients had anemia requiring ribavirin dose reduction. One patient developed hypothyroidism.</p><p id="sp4025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Conclusion.</span> Combination treatment of peginterferon alfa-2b with ribavirin appears to be efficacious and relatively safe in adolescents with chronic hepatitis C genotype R.B.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "*" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">METAVIR scoring system; ALT: alanine transferase; IV: intravenous.</p>" "identificador" => "fn1" ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 549 "Ancho" => 1588 "Tamanyo" => 63816 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Study design.</p>" ] ] 1 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 564 "Ancho" => 1000 "Tamanyo" => 112287 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Response to therapy.</p>" ] ] 2 => array:7 [ "identificador" => "t0005" "etiqueta" => "Table I" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="npara0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleFootnote" id="fn1"><span class="elsevierStyleLabel">*</span><p class="elsevierStyleNotepara" id="npar0005">METAVIR scoring system; ALT: alanine transferase; IV: intravenous.</p></span></p>" "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="left" valign="middle" scope="col">Characteristic \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="middle" scope="col">Patients (N = 12) \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="middle">Age, y, mean (range) \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="middle">15.75 (14–17) \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="middle">ALT (Ul/L), mean (range) \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="middle">91 (34–194) \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="middle">Histologic grade, mean (range)<a class="elsevierStyleCrossRef" href="#fn1">*</a> \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="middle">1.67 (1–2) \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="middle">Fibrosis score, mean (range)<a class="elsevierStyleCrossRef" href="#fn1">*</a> \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="middle">0.67 (0–3) \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="middle">HCV RNA × 10<span class="elsevierStyleSup">6</span> lU/Ml, mean (range) \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="middle">078025 (0.23–1.8) \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="middle">Risk factor, n (%) \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="middle"> \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="middle">Dental procedures \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="middle">2 (17) \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="middle">Trnasfusion \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="middle">1 (8) \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="middle">IV drug use \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="middle">2 (17) \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="middle">Vertical transmission \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="middle">2 (17) \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="middle">Unknown \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="middle">5 (42) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2078578.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics.</p>" ] ] 3 => array:7 [ "identificador" => "t0010" "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="left" valign="middle" scope="col">Adverse event \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="middle" scope="col">Incidence (%) \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="middle">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="middle">12 (100) \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="middle">Myalgia \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="middle">7 (58) \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="middle">Insomnia \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="middle">1 (8) \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="middle">Hipothyroidism \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="middle">1 (8) \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="middle">Type 1 diabetes mellitus \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="middle">1 (8) \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="middle">Anemia < 10 g/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="middle">4 (33) \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="middle">Nautropenia \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="middle">2 (17) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2078577.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Treatment-emergent events.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "Reference" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0005" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus (HCV) infection in a community in the Nile Delta: population description and HCV prevalence" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Abdel-Aziz F." 1 => "Habib M." 2 => "Mohamed M.K." 3 => "Abdel-Hamid M." 4 => "Gamil F." 5 => "Madkour S." 6 => "Mikhail N.N." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/jhep.2000.8438" "Revista" => array:6 [ "tituloSerie" => "Hepatology" "fecha" => "2000" "volumen" => "32" "paginaInicial" => "111" "paginaFinal" => "115" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10869297" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic epidemiology of hepatitis C virus throughout Egypt" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Ray S.C." 1 => "Arthur R.R." 2 => "Carella A." 3 => "Bukh J." 4 => "Thomas D.L." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1086/315786" "Revista" => array:6 [ "tituloSerie" => "J Infect Dis" "fecha" => "2000" "volumen" => "182" "paginaInicial" => "698" "paginaFinal" => "707" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10950762" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3." 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Long-term course of chronic hepatitis C in children: from viral clearance to endstage liver disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:7 [ 0 => "Bortolotti F." 1 => "Verucchi G." 2 => "Cammà C." 3 => "Cabibbo G." 4 => "Zancan L." 5 => "Indolfi G." 6 => "Giacchino R." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2008.02.082" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2008" "volumen" => "134" "paginaInicial" => "1900" "paginaFinal" => "1907" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18439604" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5." 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| 2024 November | 2 | 0 | 2 |
| 2024 October | 12 | 8 | 20 |
| 2024 September | 13 | 3 | 16 |
| 2024 August | 13 | 2 | 15 |
| 2024 July | 13 | 1 | 14 |
| 2024 June | 8 | 2 | 10 |
| 2024 May | 9 | 1 | 10 |
| 2024 April | 5 | 5 | 10 |
| 2024 March | 15 | 4 | 19 |
| 2024 February | 10 | 5 | 15 |
| 2024 January | 7 | 5 | 12 |
| 2023 December | 7 | 4 | 11 |
| 2023 November | 9 | 1 | 10 |
| 2023 October | 18 | 5 | 23 |
| 2023 September | 13 | 3 | 16 |
| 2023 August | 19 | 4 | 23 |
| 2023 July | 11 | 3 | 14 |
| 2023 June | 19 | 5 | 24 |
| 2023 May | 40 | 5 | 45 |
| 2023 April | 47 | 1 | 48 |
| 2023 March | 36 | 2 | 38 |
| 2023 February | 21 | 16 | 37 |
| 2023 January | 10 | 11 | 21 |
| 2022 December | 11 | 6 | 17 |
| 2022 November | 16 | 8 | 24 |
| 2022 October | 8 | 12 | 20 |
| 2022 September | 8 | 17 | 25 |
| 2022 August | 38 | 7 | 45 |
| 2022 July | 49 | 5 | 54 |
| 2022 June | 38 | 3 | 41 |
| 2022 May | 19 | 7 | 26 |
| 2022 April | 19 | 13 | 32 |
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| 2022 February | 40 | 7 | 47 |
| 2022 January | 62 | 5 | 67 |
| 2021 December | 51 | 12 | 63 |
| 2021 November | 27 | 4 | 31 |
| 2021 October | 53 | 10 | 63 |
| 2021 September | 43 | 9 | 52 |
| 2021 August | 19 | 6 | 25 |
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| 2021 June | 12 | 10 | 22 |
| 2021 May | 31 | 11 | 42 |
| 2021 April | 93 | 11 | 104 |
| 2021 March | 26 | 3 | 29 |
| 2021 February | 37 | 8 | 45 |
| 2021 January | 30 | 9 | 39 |
| 2020 December | 30 | 4 | 34 |
| 2020 November | 22 | 6 | 28 |
| 2020 October | 15 | 8 | 23 |
| 2020 September | 23 | 3 | 26 |
| 2020 August | 9 | 4 | 13 |
| 2020 July | 8 | 2 | 10 |
| 2020 June | 7 | 2 | 9 |
| 2020 May | 11 | 10 | 21 |
| 2020 April | 23 | 2 | 25 |
| 2020 March | 24 | 5 | 29 |
| 2020 February | 16 | 1 | 17 |
| 2020 January | 2 | 2 | 4 |
| 2019 December | 6 | 5 | 11 |
| 2019 November | 7 | 3 | 10 |
| 2019 October | 1 | 2 | 3 |
| 2019 September | 2 | 2 | 4 |
| 2019 August | 1 | 1 | 2 |
| 2019 July | 2 | 5 | 7 |
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