Extrahepatic manifestations of HCV where do we stand? | Medicina Clínica (English Edition)

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CV, cardiovascular; CVD, cardiovascular disease; CVR, cardiovascular risk; LDL-C, low-density lipoprotein cholesterol." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Juan Pedro-Botet, Elisenda Climent, David Benaiges, Gemma Llauradó" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Juan" "apellidos" => "Pedro-Botet" ] 1 => array:2 [ "nombre" => "Elisenda" "apellidos" => "Climent" ] 2 => array:2 [ "nombre" => "David" "apellidos" => "Benaiges" ] 3 => array:2 [ "nombre" => "Gemma" "apellidos" => "Llauradó" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775323005468" "doi" => "10.1016/j.medcli.2023.09.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775323005468?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020624000445?idApp=UINPBA00004N" "url" => "/23870206/0000016200000005/v1_202403010948/S2387020624000445/v1_202403010948/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S238702062400055X" "issn" => "23870206" "doi" => "10.1016/j.medcle.2023.12.004" "estado" => "S300" "fechaPublicacion" => "2024-03-08" "aid" => "6501" "copyright" => "Elsevier España, S.L.U." "documento" => "simple-article" "crossmark" => 1 "subdocumento" => "edi" "cita" => "Med Clin. 2024;162:228-30" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:10 [ "idiomaDefecto" => true "cabecera" => "Editorial" "titulo" => "Comprehensive assessment in heart failure" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "228" "paginaFinal" => "230" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Valoración integral en la insuficiencia cardiaca" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Francisco Javier Martín-Sánchez, Cristina Bermejo Boixareu" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Francisco Javier" "apellidos" => "Martín-Sánchez" ] 1 => array:2 [ "nombre" => "Cristina" "apellidos" => "Bermejo Boixareu" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0025775323007169" "doi" => "10.1016/j.medcli.2023.12.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775323007169?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S238702062400055X?idApp=UINPBA00004N" "url" => "/23870206/0000016200000005/v1_202403010948/S238702062400055X/v1_202403010948/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Extrahepatic manifestations of HCV where do we stand?" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "231" "paginaFinal" => "237" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Mohamed Aly Mokhles" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Mohamed Aly" "apellidos" => "Mokhles" "email" => array:1 [ 0 => "mohamad.mokhles@gmail.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "National Research Center, Internal Medicine Department, Center of Excellence for Medical Research, Egypt" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Manifestaciones extrahepáticas del VHC. ¿Dónde nos encontramos?" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2316 "Ancho" => 2970 "Tamanyo" => 503622 ] ] "descripcion" => array:1 [ "en" => "Proliferation of B lymphocytes secondary to HCV-CD81 binding. HCV E2 binds CD81 molecule expressed on B-lymphocytes, CD81 forms a costimulatory complex with CD19 and CD21 lowering the threshold required for BCR-mediated B cell proliferation inducing proliferation of naïve B cells leading to a wide autoantibody and immune-complex production. Ag: antigen, BCR: B cell antigen receptor, E2: envelope of hepatitis C virus, HCV: hepatitis C virus, IG: immunoglobulin." ] ] ] "textoCompleto" => "IntroductionPascual et al. in 1990<a class="elsevierStyleCrossRef" href="#bib0300">1</a> first described an association between hepatitis C virus (HCV) and extrahepatic manifestations (EHM), reporting two patients with mixed cryoglobulinemia (MC). EHM syndromes could represent the first signal of an HCV infection, as many patients show no hepatic symptoms, and up to 40–74% of patients infected with HCV might develop at least one EHM during the course of their disease where as many as 36 different syndromes have been reported to be related to HCV.<a class="elsevierStyleCrossRef" href="#bib0305">2</a> Sterling and Barlow divided these syndromes into those with a proven association with HCV as MC, neuropathy, arthralgias, type 1 membranoproliferative glomerulonephritis MPGN and those with a moderate association with HCV as non-cryoglobulinemia systemic vasculitis, splenic lymphoma, B-cell non-Hodgkin's lymphoma NHL, sicca syndrome, porphyria cutanea tarda, or mild association with HCV as Type 2 diabetes mellitus T2DM, autoimmune thyroiditis and lichen planus.<a class="elsevierStyleCrossRef" href="#bib0310">3</a> The high association between HCV and MC has been well established through several studies, where mixed cryoglobulins are found in 40–60% of HCV-infected patients, yet, only about 10–15% have EHM including palpable purpura, arthralgias, neuropathy, glomerulopathy and overt cryoglobulinemic vasculitis (CV),<a class="elsevierStyleCrossRefs" href="#bib0315">4,5</a> going the other way round HCV has been held accountant for 85–95% of all cases of MC.<a class="elsevierStyleCrossRefs" href="#bib0325">6,7</a> Moreover, Marie et al. in 2020 found that the concentration of cryoglobulins (CGs) is significantly higher within HCV RNA +ve patients than that within HCV Ab +ve/RNA −ve patients, while CGs concentrations did not differ significantly between HCV RNA −ve patients and non HCV subjects.<a class="elsevierStyleCrossRef" href="#bib0335">8</a>The corner stone of HCV associated EHM is HCV lymphotropism particularly B lymphocytes, with prolongation of B cell survival and production of immunoglobulin Ig with rheumatoid factor, RF activity forming immune complex with HCV antibody paving the way for cryoglobulinemia that is responsible for most of EHM of HCV including vasculitis, glomerulonephritis (GN), arthritis, and neuropathies. Thus, it could be said that HCV-related lymphoproliferative disorders, whose prototype is mixed cryoglobulinemia (MCG), represent the most closely related EHM of HCV.<a class="elsevierStyleCrossRefs" href="#bib0340">9,10</a>PathogenesisThe direct role of the virus in the pathogenesis of MCG has been emphasized where the HCV negative strand RNA (denoting replication) tested in peripheral blood and bone marrow derived lymphocytes was found in 46% of MCG patients including two with B cell non-Hodgkin's lymphoma NHL. And the same time no traces of HCV-negative strand RNA were found in patients with acute hepatitis C, chronic HCV without extrahepatic disorders, monoclonal gammopathy of undetermined significance, nor in B-NHL without MCG, which supported the contention that HCV is not specifically lymphotropic and its entry and replication in lymphoid cells is determined largely by selective interactions.<a class="elsevierStyleCrossRef" href="#bib0350">11</a>B lymphocytes stimulationDue to biological properties, HCV genomic sequences cannot be integrated into the host genome; the virus could trigger the immunological alterations only indirectly by exerting a chronic stimulus to the immune system,<a class="elsevierStyleCrossRef" href="#bib0355">12</a> where HCV infection of lymphoid tissues may represent the remote event leading to B-lymphocyte proliferation responsible for autoantibodies and immune-complex production.<a class="elsevierStyleCrossRef" href="#bib0360">13</a> The occurrence of a subset of HCV-infected patients carrying phenotypically distinct lymphoid cells implicates the existence of high affinity receptor molecules capable of mediating HCV trafficking on the surface, fusion and cell entry.<a class="elsevierStyleCrossRefs" href="#bib0350">11,14</a> HCV E2 binds CD81 molecule expressed on B-lymphocytes CD81, forms a costimulatory complex with CD19 and CD21 where colligation of the B cell antigen receptor (BCR) with any of the components of this costimulatory complex lowers the threshold required for BCR-mediated B cell proliferation, inducing proliferation of naïve B cells leading to a wide autoantibody and immune-complex production, including MC<a class="elsevierStyleCrossRef" href="#bib0365">14</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Another key player in B lymphocytes proliferation is the B lymphocyte stimulator (BLyS), also called B-cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) superfamily that is a 285 amino acid protein encoded by a gene on chromosome 13q32–34 and secreted by myeloid cells including monocytes, macrophages, dendritic and activated B-cells.<a class="elsevierStyleCrossRefs" href="#bib0370">15,16</a> It is reported to be highly expressed in autoimmune diseases characterized by B-cell over activation marking an evidence of the pivotal role of BLyS in B cell proliferation and the related hematological and autoimmune diseases. Transgenic mice overexpressing BLyS developed critical B cell proliferation in blood and marginal zones of lymph nodes, with the production of high titers of Igs, RF, anti-DNA antibodies and sometimes CGs<a class="elsevierStyleCrossRef" href="#bib0380">17</a> added to its important role in allowing the survival of autoreactive B-cells, essentially by inhibiting B-cell apoptosis.<a class="elsevierStyleCrossRef" href="#bib0385">18</a> The potential role for BLyS in HCV-related B cell proliferation has been strongly suggested by the results of 2 studies showing elevation of BLyS in HCV MC and increased (BLyS) ligand-receptor activity in HCV-induced B cell clonal disorders.<a class="elsevierStyleCrossRefs" href="#bib0380">17,19</a> In this context, it is worth noting that in the great majority of HCV-infected patients, B cells display an activated phenotype that disappears after therapeutic eradication of HCV.<a class="elsevierStyleCrossRef" href="#bib0365">14</a>Bcl-2 protoncogeneBcl-2 is a member of a family where different members interact with each other in a complex manner; some act to promote and others to inhibit apoptosis. The Bcl-2 protein protects cells from apoptosis, whereas its homologue, Bax, promotes apoptosis. Thus, the ratio of Bcl-2 to Bax is a determinant of susceptibility to apoptosis. Activation of Bcl-2 proto oncogene that leads to extended B-cell survival has been demonstrated in B-lymphocytes in 80% of HCV-related cryoglobulinemic vasculitis (CV).<a class="elsevierStyleCrossRef" href="#bib0395">20</a> Interestingly, rearrangement of the antiapoptotic B-cell lymphoma/leukemia 2 (bcl-2) gene is suggested to play a role in the pathogenesis of HCV-associated MC<a class="elsevierStyleCrossRef" href="#bib0400">21</a> as the bcl-2 gene on chromosome 18q21 is coupled with the immunoglobulin heavy chain gene (IgH) on chromosome 14q32 by a process frequently involving IgH joining segments (JH) at the junction of the two genes. Consequently, bcl-2 is activated and B cells bearing the t(14;18) translocation express elevated levels of the Bcl-2 protein.<a class="elsevierStyleCrossRef" href="#bib0405">22</a>The t(14;18) translocation, the most frequent genetic aberration in human lymphoma, may be favored by sustained, strong antigenic stimulation.<a class="elsevierStyleCrossRef" href="#bib0395">20</a> The prevalence of bcl-2 rearrangement in peripheral blood mononuclear cells was significantly higher in patients with chronic HCV infection than in healthy persons or chronic liver disease patients to other etiology,<a class="elsevierStyleCrossRef" href="#bib0400">21</a> and was particularly high in patients with HCV-associated type II MC.<a class="elsevierStyleCrossRef" href="#bib0405">22</a> Moreover, this chromosome alteration t(14;18) was completely reversed after eradication of HCV with antiviral therapy.<a class="elsevierStyleCrossRef" href="#bib0410">23</a>CryoglobulinemiaCGs are thought to be responsible for a variety of EHM associated with HCV, including vasculitis, GN, arthritis, and neuropathies, which occur in approximately 10% of HCV patients with CGs.<a class="elsevierStyleCrossRef" href="#bib0345">10</a> May be complicated by B-NHL in 10% of the cases.<a class="elsevierStyleCrossRef" href="#bib0415">24</a> From another point, HCV infection has been found in almost (91%) of patients with MC<a class="elsevierStyleCrossRef" href="#bib0360">13</a> where a causative role of HCV in over 4/5 patients has been definitely established on the basis of epidemiological, pathological, and laboratory studies.<a class="elsevierStyleCrossRef" href="#bib0355">12</a>MC results from cold-insoluble immunoglobulin complexes or CGs that precipitate in the serum of 40–50% of patients with chronic HCV infection,<a class="elsevierStyleCrossRef" href="#bib0345">10</a> that usually contain large amounts of HCV antigen and/or antibodies against HCV. Cold-dependent insolubility of HCV particles and proteins seems the result of IgM rheumatoid factor (RF) activity, which acts as incomplete cryoglobulin, in that it precipitates at low temperature in the presence of IgG with specific anti-HCV reactivity. The dynamics of cold-dependent insolubility demonstrates that the addition of an irrelevant IgG to an IgM RF/HCV proteins mixture was unable to precipitate the protein. This implies that a potentially functional RF repertoire may be positively selected by IgG anti-HCV antibodies.<a class="elsevierStyleCrossRef" href="#bib0350">11</a> CGs are classified according to their immunoglobulin clonality into; type I consists of monoclonal Igs, type II is a mixture of monoclonal and polyclonal Igs, and type III consists of polyclonal Igs.<a class="elsevierStyleCrossRef" href="#bib0420">25</a>Initially, only polyclonal CGs are produced, and then a dominant B-cell clone emerges, producing monoclonal immunoglobulins.<a class="elsevierStyleCrossRef" href="#bib0305">2</a> MC is a systemic vasculitis involving small vessels (arterioles, capillaries, venules) whose histological hallmark is leukocytoclastic vasculitis secondary to the vascular deposition of circulating immune-complexes, mainly CGs and complement. The immune-mediated vasculitic lesions are responsible for different MC clinical features, including cutaneous and visceral organ involvement.<a class="elsevierStyleCrossRef" href="#bib0415">24</a>Response of EHM of HCV to antiviral therapy (AVT)The attention to EHM of HCV has been paid as early as the dawn of HCV, prior to completion of HCV of its fourth year as a discovered hepatotropic virus an early study by Johnson and his team shed a light on the association between MPGN and HCV, as they demonstrated a dramatic reduction in proteinuria in four patients while on Interferon (IFN) treatment.<a class="elsevierStyleCrossRef" href="#bib0425">26</a> Moving to the direct acting drugs (DAAs) era several studies demonstrated an association between sustained virological response (SVR) to DAAs and resolution of EHM of HCV as porphyria cutanea tarda,<a class="elsevierStyleCrossRefs" href="#bib0430">27,28</a> disturbances in B and T cell homeostasis<a class="elsevierStyleCrossRef" href="#bib0440">29</a> and some reports indicated a possible improvement in glycemic control, HbA1c and decreased insulin use.<a class="elsevierStyleCrossRefs" href="#bib0445">30–33</a> HCV AVT was not only studied in terms of response of existing EHM to treatment, but in terms of risk reduction of developing EHM in the first place, as SVR to IFN has been associated with a reduced risk of MC, GN, porphyria cutanea tarda, NHL,<a class="elsevierStyleCrossRef" href="#bib0465">34</a> and possibly DM.<a class="elsevierStyleCrossRefs" href="#bib0470">35–38</a> Mahale and his research team in their study carried on 160,875 US veterans receiving IFN based therapy and followed up for a median of 5.1 years agreed with the previous studies in terms of risk reductions in MC, GN, porphyria cutanea tarda and DM – within patients showing SVR as compared to those who didn’t achieve SVR – but did not find risk reduction in NHL.<a class="elsevierStyleCrossRef" href="#bib0470">35</a> El Serag et al.’s study carried on DAA treated patients demonstrated similar results since a significant reduction in the risk of developing MC, GN, lichen planus, and possibly porphyria cutanea tarda was found in patients achieving SVR while there was no such risk reduction for NHL. Yet, El Serag et al.’s study discorded with Mehale's as regards the risk of developing DM which was not demonstrated in El Serag's study.<a class="elsevierStyleCrossRef" href="#bib0490">39</a>Clinical and immunological responsesAll studies since the IFN era set clinical and immunological responses as the two main parameters for evaluating the response of EHM of HCV to AVT, which could be exemplified as a canvas of clinical response knitted on a background of immunological response framed by SVR.Saadoun et al. in their early study followed up 72 patients treated with IFN+Ribavirin who achieved an SVR of 58% and complete clinical response – defined as resolution of vaculitis – in 62.5%, for 39.7±24.4 months after end of therapy. As for different clinical manifestations, purpura was found to resolve in 86%, arthralgia in 80%, peripheral neuropathy in 68% and renal involvement in 41%. From the immunological aspect, cryoglobulins cleared in 45.8% of patient, cryoglobulin level decreased from a mean of 1.15g/l to 0.27g/l (P<0.001), C4 complement level normalized in 70% (P<0.001), and rheumatoid factor disappeared in 17.8% of patients (P=0.01). There was an association between the clearance of cryoglobulins, clearance of RF (P=0.003) and normalization of the C4 level (P=0.01). Cryoglobulinemia, eGFR, and proteinuria were significantly improved in the SVR group in comparison to the non virological responder group. It is noteworthy that 6 out of 8 virological relapsed 2 months after end of treatment and was associated with cryoglobulinemic vasculitis (CV) relapse as well.<a class="elsevierStyleCrossRef" href="#bib0495">40</a>In the era of DAAs, EHM response to AVT did not seem to differ much despite tremendous increase in virological response. Bonacci and his group<a class="elsevierStyleCrossRef" href="#bib0500">41</a> on a background of SVR 94% demonstrated 71% complete clinical response of patients with CV which was associated with viral eradication, and 48% immunological response – defined by the study group as undetectable cryoglobulins and complement and rheumatoid factor normalization – which was not associated with SVR. Markers of immune activation persisted in 52% of patients, while baseline cryocrit level seemed to be the determinant factor for immunological response as a baseline of <2.7% was the only factor associated with complete immunological response on multivariate analysis. Owing to the findings that, immune activation persistence did not differ significantly between CV patients and those with asymptomatic circulating cryoglobulins (ACC), only 37% of clinical responders attained immunological improvement, and 73% of immunological responders had clinical improvement, a question may be imposed. Could persistence of immune activation be the trigger of clinical relapse serving as a fire under the straw?.Complete clinical response defined as normalization of vasculitic manifestations and partial response defined as reduction of >50% of vasculitic manifestations were reached in 38% and 22% of symptomatic patients respectively, in Emery et al.’s retrospective study carried on 18 symptomatic and 65 asymptomatic patients treated with DAA±Peg IFN.<a class="elsevierStyleCrossRef" href="#bib0505">42</a> Interestingly, cryoglobulins disappeared in 29.4% symptomatic and 52.9% asymptomatic patients, while SVR did not show significant difference between symptomatic 88.9% and asymptomatic 90.8% patients, which opens a research horizon for exploring possible other players than virological response contributing to immunological response.Is there a need for adjuvant treatment?Half of the patients show definite clinical improvements of vasculitis, while renal diseases and lympho-proliferative disorders appear to have a lower remission rate after viral eradication with DAAs and most cases needed immunosuppressive treatments.<a class="elsevierStyleCrossRef" href="#bib0510">43</a> The introduction of the anti CD 20 monoclonal antibody rituximab as an adjuvant to treatment since the IFN era is based on the concept that treatment of HCV EHM involves targeting B cell expansion.<a class="elsevierStyleCrossRef" href="#bib0515">44</a> Rituximab adjunction had shown improved clinical outcomes compared to AVT, in terms of a shorter time to clinical remission (5.4±4 vs 8.4±4.7 months, P=.004), better renal response rates (80.9% vs 40% of complete response, P=.040), as well as immunological outputs in terms of higher rates of cryoglobulin clearance (68.4% vs 43.6%, P=.001) and clonal VH1-69+ B-cell suppression (P<.01).<a class="elsevierStyleCrossRef" href="#bib0520">45</a> Nevertheless, Sise et al. demonstrated an improvement of eGFR and reduction in proteinuria in patients with active GN who were successfully treated with sofosbuvir plus simeprevir – showing an SVR of 83% – particularly in those whose onset of proteinuria was recent. Several patients could decrease immunosuppression, while a single patient was in need to increase immunosuppression and it happened that he had a virologic relapse. A complete immunological response was reached in 44% of patients, with median percent decreasing from 1.5% to 0.5% reaching a nadir at a median of 4.6 months (range 22 days–13 months) as per protocol.<a class="elsevierStyleCrossRef" href="#bib0525">46</a> This complete response which was found to be permanent in a case report of severe HCV-MCV case treated with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin.<a class="elsevierStyleCrossRef" href="#bib0530">47</a>Does response build up by time?Although a 15-month follow-up study revealed a complete clinical response rate of 72.6%, defined as improvement of all organs involved at baseline and the absence of clinical relapse, which is equivalent to rates in studies of shorter follow-up duration. There was a 22.6% partial response, defined as improvement in some but not all organs involved at baseline, and a 4.8% non-response. Factors associated with partial or no response were severe form of CV and peripheral neuropathy. When breaking down the clinical manifestations, purpura was cleared in 97.2% of patients, renal involvement in 91.5% of patients, arthralgia in 85.7% of patients, and neuropathy in 77.1% of patients. Regarding the immunologic response, 53.1% of patients cleared cryoglobulins in blood samples.<a class="elsevierStyleCrossRef" href="#bib0535">48</a> However, the results of Gragnani et al.’s study 50 were more meaningful as they tracked the response of EHM to AVT longitudinally rather than obtaining a cross-sectional snapshot. At week 12 post-treatment, they found that 34% were full complete responders clearing all manifestations of vasculitis; 32% were complete responders, showing improvement in all manifestations of vasculitis; 27% were partial responders, experiencing disappearance or improvement of at least half of the manifestations of vasculitis. 7% were non-responders, showing disappearance or improvement of fewer than half of the baseline symptoms. On extending the follow-up to week 24 post-treatment, the percentage of full complete responders increased to 36%, complete responders to 41%, and as a result, partial responders dropped to 24%. Furthermore, the Birmingham Vasculitis Activity Score significantly decreased from 5.41 (±3.53) at baseline to 2.35 (±2.25) at week 4 of treatment, to 1.39 (±1.48) at week 12 post-treatment, and to 1.27 (±1.68) at week 24 post-treatment. It is noteworthy that two patients with partial regression of the symptoms of vasculitis and decrease in the cryocrit level at week 24 after end of therapy developed indolent lymphoma with monoclonal B cell lymphocytosis during the study. By the end of the study, purpura disappeared in 87.5% of patients, arthralgia in 46%, weakness in 56%, peripheral neuropathy in 50%, and renal involvement in 75%. In terms of the immunological response, the mean cryocrit value significantly decreased from 7.2% (±15.4%) at baseline to 2.9% (±7.4%) at 12 weeks post-treatment, and further to 1.8% (±5.1%) at 24 weeks post-treatment. Similarly, a complete immunological response, defined as the disappearance of cryoglobulins, was achieved by 32% of patients at week 12 post-treatment, increasing to 39.5% at week 24 post-treatment. A partial response, defined as a <50% decrease in cryocrit, was achieved by 39% of patients at week 12 post-treatment, but dropped to 34% at week 24 post-treatment. A null response, defined as a <50% decrease in cryocrit, was found in 29% at week 12 post-treatment, decreasing to 26.5% at week 24 post-treatment. RF levels decreased from 131.2±252.9 at baseline to 66.2±91.8 at week 12 post-treatment and to 39.0±29.8 at 24 weeks post-treatment. The findings of this study clearly demonstrate that clinical and immunological responses develop over time (<a class="elsevierStyleCrossRefs" href="#fig0010">Figs. 2 and 3</a>), which necessitates more longitudinal clinical studies for longer durations to determine whether the elapsed time post-treatment is a factor in relapse or remission. Additionally, it is important to investigate whether there is a time in which the response peaks and whether extending the treatment duration may affect the response rate.<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>To sum up a particular pattern for the response of different clinical manifestations of systemic vasculitis secondary to HCV could not be deduced from available clinical studies as demonstrated in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, which could be attributed to lack of head to head studies and the lack of homogeneity in terms of the duration of treatment and types of antiviral medications used. Also, complete clinical response showed variation between different clinical studies as it ranged from 34% to 71%, while immunological response defined as clearance of cryoglobulins was less variable between different studies as it ranged between 32% and 48%, as shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Response of lymphomas to AVTThe strongest worldwide epidemiological association between non-hepatocellular malignancies and HCV was found to be with lymphoproliferative diseases, particularly B-NHL.<a class="elsevierStyleCrossRefs" href="#bib0545">50–52</a> The role of HCV antiviral therapy in the treatment of HCV-associated lymphoproliferative disorders, as well as the positive correlation between virological and hematological responses, has been well established since the IFN era.<a class="elsevierStyleCrossRef" href="#bib0560">53</a> Interestingly, a case of refractory mantle cell lymphoma (MCL) that was resistant to chlorambucil, splenectomy, rituximab, and seven cycles of fludarabine and mitoxantrone achieved complete remission with an undetectable HCV viral load within 1 month of treatment with ribavirin and IFN.<a class="elsevierStyleCrossRef" href="#bib0565">54</a>Successful role of the anti HCV viral therapy in treating HCV associated lymphoproliferative disorders continued through the very first steps of the DAAs era, when DAAs were added to IFN. Michot et al. investigated the role of AVT in 116 HCV-associated B-cell lymphoma patients of different histological types mid zonal lymphoma (MZL), diffuse large B cell lymphoma (DLBCL), and other types, 64 of which were treated with IFN+Ribavirin and only 6 received a protease inhibitor in addition. SVR of 61% was achieved which did not differ between different histological types. Three-year overall survival (OS) and progression free survival were (PFS) 78% [95% CI (63–88)] and 64% [95% CI (48–67)] respectively, without differences between cytohistological groups.As for hematological response, 78% of MZL patients receiving AVT alone as first-line treatment achieved an overall hematological response, and 57% showed complete response (CR), defined as the disappearance of all evidence of disease. All responders also showed sustained virological response (SVR), while the 22% non-responders were non-virological responders as well. Patients treated with AVT-Rituximab combination regimen showed a 62.5% CR, and those treated with chemotherapy±rituximab showed a 43% CR. DLBCL patients received front-line immune-chemotherapy with no patients receiving AVT in combination, resulting in an 80% CR.<a class="elsevierStyleCrossRef" href="#bib0570">55</a> It is important to note that despite incorporating a DAA into AVT, the results of this study could not be used to evaluate the role of DAAs in lymphoma treatment, as only 6 out of 70 patients (8.5%) receiving AVT had a DAA in addition. It is also noteworthy that patients with DLBCL did not receive the same front-line treatment as those with MZL, making an accurate comparison between the responses of different types of lymphoma to treatment unattainable. As part of HCV AVT evolution, DAAs were used solely without combination with IFN, and the response of lymphoproliferative disorders did not differ based on the antiviral therapy used.<a class="elsevierStyleCrossRef" href="#bib0575">56</a>One study demonstrated that SVR 12 was achieved in 98% of patients treated with DAAs, with an overall lymphoproliferative disease response (LDR) of 67%, including 26% complete responders. The highest response was observed among MZL patients, who showed a 73% response. Intriguingly, patients with chronic lymphocytic lymphoma (CLL) and small lymphocytic lymphoma (SLL) showed no response. The 1-year progression-free survival (PFS) and overall survival (OS) rates were as high as 75% (95% confidence interval [CI], 51–88) and 98% (95% CI, 86–100), respectively.<a class="elsevierStyleCrossRef" href="#bib0580">57</a> Similar results were later obtained by Frigeni et al. in 2019 in a series of 100 patients, showing an overall response rate (ORR) of 66%, with 23% achieving CR. The response rate was higher in MZL compared to non-MZL (ORR 73% vs. 48%, P=0.021; CR 30% vs. 7%, and partial response (PR) 44% vs. 41%, respectively), with worse lymphoma response in patients with nodal involvement. No hematological response was documented in patients with CLL/SLL.<a class="elsevierStyleCrossRef" href="#bib0585">58</a>Lin et al. raised concerns as they reported two patients treated with sofosbuvir/ribavirin who cleared the virus but developed de novo aggressive mantle cell lymphoma (MCL) one month after the end of therapy.<a class="elsevierStyleCrossRef" href="#bib0590">59</a> Furthermore, the progression of lymphoma after DAAs has been observed, with six out of 100 patients progressing within three months from the end of DAAs. One of them transformed from splenic MZL to DLBCL. Seven patients progressed between three and 12 months from the start of AVT, and three patients progressed thereafter. Interestingly, progression did not correlate with the pattern of initial response, whether partial or complete.<a class="elsevierStyleCrossRef" href="#bib0585">58</a> This highlights the findings from the aforementioned study by Gragnani et al., where two patients showing partial clinical response developed indolent lymphoma with monoclonal B cell lymphocytosis despite having a 50% decrease in cryocrit level.<a class="elsevierStyleCrossRef" href="#bib0545">50</a> These findings emphasize the importance of post-DAAs follow-up for early detection of de novo lymphoma or progression of existing ones.ConclusionsTransitioning from IFN-based therapy to the era of DAAs has yielded favorable results in terms of SVR and side effects. However, the response of EHM does not seem to follow the same pattern and appears to be more complex. Therefore, there is still a need for adjuvant therapy, such as the use of anti-CD20 Rituximab in specific cases. To accurately assess EHM response to AVT, longitudinal studies would be more preferable than cross-sectional ones, as some studies have shown improvement in response over time after cessation of therapy, while others have shown a relapsing pattern. Thus, there is an imperative need for longitudinal clinical studies. Additionally, it would be beneficial if clinical practice guidelines include plans for EHM follow-up post-AVT, addressing response, relapse, and safety concerns. It is noteworthy that reports have pointed to the progression of preexisting lymphoma post-AVT. Finally, confounding factors influencing EHM response to AVT need to be extensively studied as this could refine management and improve overall response rates.Authors’ contributionThe single author of the article contributed by reviewing the literature and gathering the scientific content and writing the manuscript.Ethical considerationInformed consent is not applicable to this work as it is a review article.Data availability statementThe data included in this review article could be accessed via the references section.FundingThere is no financial support for this article.Conflict of interestThere is no conflict of interest for this article." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres2098876" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1788387" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2098875" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1788388" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:6 [ 0 => array:3 [ "identificador" => "sec0010" "titulo" => "Pathogenesis" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "B lymphocytes stimulation" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Bcl-2 protoncogene" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Cryoglobulinemia" ] ] ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Response of EHM of HCV to antiviral therapy (AVT)" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Clinical and immunological responses" ] 3 => array:2 [ "identificador" => "sec0040" "titulo" => "Is there a need for adjuvant treatment?" ] 4 => array:2 [ "identificador" => "sec0045" "titulo" => "Does response build up by time?" ] 5 => array:2 [ "identificador" => "sec0050" "titulo" => "Response of lymphomas to AVT" ] ] ] 5 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 6 => array:2 [ "identificador" => "sec0060" "titulo" => "Authors’ contribution" ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Ethical consideration" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Data availability statement" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-07-07" "fechaAceptado" => "2023-10-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1788387" "palabras" => array:5 [ 0 => "Extrahepatic manifestations" 1 => "HCV" 2 => "Cryoglobulinemia" 3 => "DAAs" 4 => "Cryoglobulinemic vasculitis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1788388" "palabras" => array:5 [ 0 => "Manifestaciones extrahepáticas" 1 => "VHC" 2 => "Crioglobulinemia" 3 => "AAD" 4 => "Vasculitis crioglobulinémica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Hepatitis C virus (HCV) infection has been associated as up 40–70% of patients with extrahepatic manifestations (EHM) and 36 different syndromes. These could be attributed to the fact that HCV is lymphotropic, particularly B lymphotropic, and not merely hepatotropic, and could trigger immunological alterations indirectly by exerting a chronic stimulus on the immune system with production of immunoglobulins having rheumatoid activity forming immune complexes and production of cryoglobulins. Cryoglobulinemoa plays a pivotal role in producing most EHM of HCV such as vasculitis, glomerulonephritis, arthritis and neuropathies. Less frequently; while less frequently, the direct viral cytopathic effect could lead to EHMs independent of cryoglobulinemia. The mainstay of treatment of EMH has been antivirals, since interferon era to direct-acting drugs era, with no differences between the two eras, despite the better virological response. Longer evaluation of virological response and clinical investigation with longer follow-ups are necessary." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La infección por el virus hepatitis C (VHC) se ha asociado a 40-70% de los pacientes con alguna manifestación extrahepática (MEH) y 36 síndromes diferentes, atribuibles a que el VHC es linfotrópico, particularmente linfotrópico B, y no simplemente hepatotrópico. El VHC podría desencadenar alteraciones inmunológicas al ejercer un estímulo crónico del sistema inmunológico con producción de inmunoglobulinas con actividad reumatoide y formación de complejos inmunes y crioglobulinas. Estas desempeñan un papel fundamental en la mayoría de las MEH como vasculitis, glomerulonefritis, artritis y neuropatías, mientras, menos frecuentemente, el efecto citopático viral directo podría conducir a MEH independientes de crioglobulinas. El principal tratamiento de las MEH ha sido el antiviral, desde la era del interferón hasta la de los fármacos de acción directa, sin diferencias entre las dos épocas, a pesar de la mejor respuesta virológica. Son necesarias evaluaciones más prolongadas de la respuesta virológica e investigación clínica con seguimientos más largos." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2316 "Ancho" => 2970 "Tamanyo" => 503622 ] ] "descripcion" => array:1 [ "en" => "Proliferation of B lymphocytes secondary to HCV-CD81 binding. HCV E2 binds CD81 molecule expressed on B-lymphocytes, CD81 forms a costimulatory complex with CD19 and CD21 lowering the threshold required for BCR-mediated B cell proliferation inducing proliferation of naïve B cells leading to a wide autoantibody and immune-complex production. Ag: antigen, BCR: B cell antigen receptor, E2: envelope of hepatitis C virus, HCV: hepatitis C virus, IG: immunoglobulin." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1373 "Ancho" => 2346 "Tamanyo" => 166205 ] ] "descripcion" => array:1 [ "en" => "Follow up of clinical response post DAA therapy in Gragnani study.<a class="elsevierStyleCrossRef" href="#bib0540">49</a>Full complete response: clearance of all manifestations of vasculitis, complete response: improvement of all the manifestations of vasculiti, partial response: disappearance or improvement of at least half of the manifestations of vasculitis, complete immunological response: disappearance of cryoglobulins." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1373 "Ancho" => 2346 "Tamanyo" => 144706 ] ] "descripcion" => array:1 [ "en" => "Dynamics of immunological parameters and vasculitis activity in response to DAA therapy Gragnani study.<a class="elsevierStyleCrossRef" href="#bib0540">49</a> Cryocrit is expressed percentage, rheumatoid factor in IU/ml. BVAS: Birmingham vasculitis activity score." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AVT: antiviral therapy." "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="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \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">AVT \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">Purpura \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">Arthritis \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">Renal \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">Neuropathy \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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Saadoun et al., 2006<a class="elsevierStyleCrossRef" href="#bib0495">40</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="\n \t\t\t\t\ttop\n \t\t\t\t">IFN \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">80% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">68% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cacoub et al., 2019<a class="elsevierStyleCrossRef" href="#bib0535">48</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="\n \t\t\t\t\ttop\n \t\t\t\t">DAAs \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">97.2% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">85.7% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">91.5% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">77% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Graganini et al., 2016<a class="elsevierStyleCrossRef" href="#bib0540">49</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="\n \t\t\t\t\ttop\n \t\t\t\t">DAAs \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">87.5% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">75% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3473079.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Resolution of different clinical manifestations in different studies." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AVT: antiviral therapy, CCR: complete clinical response, CIR: complete immunological response, SVR: sustained virological response." "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="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \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">AVT \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">SVR \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">CCR \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">CIR \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">Follow up \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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bonacci et al., 2017<a class="elsevierStyleCrossRef" href="#bib0515">44</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="\n \t\t\t\t\ttop\n \t\t\t\t">DAAs \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">71% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">48% \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 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Emery et al., 2017<a class="elsevierStyleCrossRef" href="#bib0520">45</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="\n \t\t\t\t\ttop\n \t\t\t\t">DAAs+Peg IFN \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">90.8% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38.8% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29.4% \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">12 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sise et al., 2016<a class="elsevierStyleCrossRef" href="#bib0555">52</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="\n \t\t\t\t\ttop\n \t\t\t\t">DAAs \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="" 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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44% \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 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gragnani et al., 2016<a class="elsevierStyleCrossRef" href="#bib0530">47</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="\n \t\t\t\t\ttop\n \t\t\t\t">DAAs \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">36% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39.5% \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">24 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cacoub et al., 2019<a class="elsevierStyleCrossRef" href="#bib0535">48</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="\n \t\t\t\t\ttop\n \t\t\t\t">DAAs \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">97.2% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72.6% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">53.1% \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 months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Saadoun et al., 2006<a class="elsevierStyleCrossRef" href="#bib0510">43</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="\n \t\t\t\t\ttop\n \t\t\t\t">IFN \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62.5% \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45.8% \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">39±24 months \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3473080.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Complete immunological and clinical responses to antiviral therapies in different studies." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:59 [ 0 => array:3 [ "identificador" => "bib0300" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatitis C virus in patients with cryoglobulinemia type II" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. 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Extrahepatic manifestations of HCV where do we stand?

Manifestaciones extrahepáticas del VHC. ¿Dónde nos encontramos?

Mohamed Aly Mokhles

National Research Center, Internal Medicine Department, Center of Excellence for Medical Research, Egypt

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pascual et al&#46; in 1990<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">1</span></a> first described an association between hepatitis C virus &#40;HCV&#41; and extrahepatic manifestations &#40;EHM&#41;&#44; reporting two patients with mixed cryoglobulinemia &#40;MC&#41;&#46; EHM syndromes could represent the first signal of an HCV infection&#44; as many patients show no hepatic symptoms&#44; and up to 40&#8211;74&#37; of patients infected with HCV might develop at least one EHM during the course of their disease where as many as 36 different syndromes have been reported to be related to HCV&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">2</span></a> Sterling and Barlow divided these syndromes into those with a proven association with HCV as MC&#44; neuropathy&#44; arthralgias&#44; type 1 membranoproliferative glomerulonephritis MPGN and those with a moderate association with HCV as non-cryoglobulinemia systemic vasculitis&#44; splenic lymphoma&#44; B-cell non-Hodgkin&#39;s lymphoma NHL&#44; sicca syndrome&#44; porphyria cutanea tarda&#44; or mild association with HCV as Type 2 diabetes mellitus T2DM&#44; autoimmune thyroiditis and lichen planus&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">3</span></a> The high association between HCV and MC has been well established through several studies&#44; where mixed cryoglobulins are found in 40&#8211;60&#37; of HCV-infected patients&#44; yet&#44; only about 10&#8211;15&#37; have EHM including palpable purpura&#44; arthralgias&#44; neuropathy&#44; glomerulopathy and overt cryoglobulinemic vasculitis &#40;CV&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">4&#44;5</span></a> going the other way round HCV has been held accountant for 85&#8211;95&#37; of all cases of MC&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">6&#44;7</span></a> Moreover&#44; Marie et al&#46; in 2020 found that the concentration of cryoglobulins &#40;CGs&#41; is significantly higher within HCV RNA &#43;ve patients than that within HCV Ab &#43;ve&#47;RNA &#8722;ve patients&#44; while CGs concentrations did not differ significantly between HCV RNA &#8722;ve patients and non HCV subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">8</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The corner stone of HCV associated EHM is HCV lymphotropism particularly B lymphocytes&#44; with prolongation of B cell survival and production of immunoglobulin Ig with rheumatoid factor&#44; RF activity forming immune complex with HCV antibody paving the way for cryoglobulinemia that is responsible for most of EHM of HCV including vasculitis&#44; glomerulonephritis &#40;GN&#41;&#44; arthritis&#44; and neuropathies&#46; Thus&#44; it could be said that HCV-related lymphoproliferative disorders&#44; whose prototype is mixed cryoglobulinemia &#40;MCG&#41;&#44; represent the most closely related EHM of HCV&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">9&#44;10</span></a></p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pathogenesis</span><p id="par0015" class="elsevierStylePara elsevierViewall">The direct role of the virus in the pathogenesis of MCG has been emphasized where the HCV negative strand RNA &#40;denoting replication&#41; tested in peripheral blood and bone marrow derived lymphocytes was found in 46&#37; of MCG patients including two with B cell non-Hodgkin&#39;s lymphoma NHL&#46; And the same time no traces of HCV-negative strand RNA were found in patients with acute hepatitis C&#44; chronic HCV without extrahepatic disorders&#44; monoclonal gammopathy of undetermined significance&#44; nor in B-NHL without MCG&#44; which supported the contention that HCV is not specifically lymphotropic and its entry and replication in lymphoid cells is determined largely by selective interactions&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">11</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">B lymphocytes stimulation</span><p id="par0020" class="elsevierStylePara elsevierViewall">Due to biological properties&#44; HCV genomic sequences cannot be integrated into the host genome&#59; the virus could trigger the immunological alterations only indirectly by exerting a chronic stimulus to the immune system&#44;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">12</span></a> where HCV infection of lymphoid tissues may represent the remote event leading to B-lymphocyte proliferation responsible for autoantibodies and immune-complex production&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">13</span></a> The occurrence of a subset of HCV-infected patients carrying phenotypically distinct lymphoid cells implicates the existence of high affinity receptor molecules capable of mediating HCV trafficking on the surface&#44; fusion and cell entry&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">11&#44;14</span></a> HCV E2 binds CD81 molecule expressed on B-lymphocytes CD81&#44; forms a costimulatory complex with CD19 and CD21 where colligation of the B cell antigen receptor &#40;BCR&#41; with any of the components of this costimulatory complex lowers the threshold required for BCR-mediated B cell proliferation&#44; inducing proliferation of na&#239;ve B cells leading to a wide autoantibody and immune-complex production&#44; including MC<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Another key player in B lymphocytes proliferation is the B lymphocyte stimulator &#40;BLyS&#41;&#44; also called B-cell activating factor &#40;BAFF&#41;&#44; a member of the tumor necrosis factor &#40;TNF&#41; superfamily that is a 285 amino acid protein encoded by a gene on chromosome 13q32&#8211;34 and secreted by myeloid cells including monocytes&#44; macrophages&#44; dendritic and activated B-cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">15&#44;16</span></a> It is reported to be highly expressed in autoimmune diseases characterized by B-cell over activation marking an evidence of the pivotal role of BLyS in B cell proliferation and the related hematological and autoimmune diseases&#46; Transgenic mice overexpressing BLyS developed critical B cell proliferation in blood and marginal zones of lymph nodes&#44; with the production of high titers of Igs&#44; RF&#44; anti-DNA antibodies and sometimes CGs<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">17</span></a> added to its important role in allowing the survival of autoreactive B-cells&#44; essentially by inhibiting B-cell apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">18</span></a> The potential role for BLyS in HCV-related B cell proliferation has been strongly suggested by the results of 2 studies showing elevation of BLyS in HCV MC and increased &#40;BLyS&#41; ligand-receptor activity in HCV-induced B cell clonal disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">17&#44;19</span></a> In this context&#44; it is worth noting that in the great majority of HCV-infected patients&#44; B cells display an activated phenotype that disappears after therapeutic eradication of HCV&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Bcl-2 protoncogene</span><p id="par0030" class="elsevierStylePara elsevierViewall">Bcl-2 is a member of a family where different members interact with each other in a complex manner&#59; some act to promote and others to inhibit apoptosis&#46; The Bcl-2 protein protects cells from apoptosis&#44; whereas its homologue&#44; Bax&#44; promotes apoptosis&#46; Thus&#44; the ratio of Bcl-2 to Bax is a determinant of susceptibility to apoptosis&#46; Activation of Bcl-2 proto oncogene that leads to extended B-cell survival has been demonstrated in B-lymphocytes in 80&#37; of HCV-related cryoglobulinemic vasculitis &#40;CV&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">20</span></a> Interestingly&#44; rearrangement of the antiapoptotic B-cell lymphoma&#47;leukemia 2 &#40;<span class="elsevierStyleItalic">bcl-2</span>&#41; gene is suggested to play a role in the pathogenesis of HCV-associated MC<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> as the <span class="elsevierStyleItalic">bcl-2</span> gene on chromosome 18q21 is coupled with the immunoglobulin heavy chain gene &#40;IgH&#41; on chromosome 14q32 by a process frequently involving IgH joining segments &#40;<span class="elsevierStyleItalic">J</span><span class="elsevierStyleInf">H</span>&#41; at the junction of the two genes&#46; Consequently&#44; <span class="elsevierStyleItalic">bcl-2</span> is activated and B cells bearing the <span class="elsevierStyleItalic">t</span>&#40;14&#59;18&#41; translocation express elevated levels of the Bcl-2 protein&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">t</span>&#40;14&#59;18&#41; translocation&#44; the most frequent genetic aberration in human lymphoma&#44; may be favored by sustained&#44; strong antigenic stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">20</span></a> The prevalence of <span class="elsevierStyleItalic">bcl-2</span> rearrangement in peripheral blood mononuclear cells was significantly higher in patients with chronic HCV infection than in healthy persons or chronic liver disease patients to other etiology&#44;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">21</span></a> and was particularly high in patients with HCV-associated type II MC&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">22</span></a> Moreover&#44; this chromosome alteration <span class="elsevierStyleItalic">t</span>&#40;14&#59;18&#41; was completely reversed after eradication of HCV with antiviral therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Cryoglobulinemia</span><p id="par0040" class="elsevierStylePara elsevierViewall">CGs are thought to be responsible for a variety of EHM associated with HCV&#44; including vasculitis&#44; GN&#44; arthritis&#44; and neuropathies&#44; which occur in approximately 10&#37; of HCV patients with CGs&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">10</span></a> May be complicated by B-NHL in 10&#37; of the cases&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">24</span></a> From another point&#44; HCV infection has been found in almost &#40;91&#37;&#41; of patients with MC<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">13</span></a> where a causative role of HCV in over 4&#47;5 patients has been definitely established on the basis of epidemiological&#44; pathological&#44; and laboratory studies&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">12</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">MC results from cold-insoluble immunoglobulin complexes or CGs that precipitate in the serum of 40&#8211;50&#37; of patients with chronic HCV infection&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">10</span></a> that usually contain large amounts of HCV antigen and&#47;or antibodies against HCV&#46; Cold-dependent insolubility of HCV particles and proteins seems the result of IgM rheumatoid factor &#40;RF&#41; activity&#44; which acts as incomplete cryoglobulin&#44; in that it precipitates at low temperature in the presence of IgG with specific anti-HCV reactivity&#46; The dynamics of cold-dependent insolubility demonstrates that the addition of an irrelevant IgG to an IgM RF&#47;HCV proteins mixture was unable to precipitate the protein&#46; This implies that a potentially functional RF repertoire may be positively selected by IgG anti-HCV antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">11</span></a> CGs are classified according to their immunoglobulin clonality into&#59; type I consists of monoclonal Igs&#44; type II is a mixture of monoclonal and polyclonal Igs&#44; and type III consists of polyclonal Igs&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">25</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Initially&#44; only polyclonal CGs are produced&#44; and then a dominant B-cell clone emerges&#44; producing monoclonal immunoglobulins&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">2</span></a> MC is a systemic vasculitis involving small vessels &#40;arterioles&#44; capillaries&#44; venules&#41; whose histological hallmark is leukocytoclastic vasculitis secondary to the vascular deposition of circulating immune-complexes&#44; mainly CGs and complement&#46; The immune-mediated vasculitic lesions are responsible for different MC clinical features&#44; including cutaneous and visceral organ involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">24</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Response of EHM of HCV to antiviral therapy &#40;AVT&#41;</span><p id="par0055" class="elsevierStylePara elsevierViewall">The attention to EHM of HCV has been paid as early as the dawn of HCV&#44; prior to completion of HCV of its fourth year as a discovered hepatotropic virus an early study by Johnson and his team shed a light on the association between MPGN and HCV&#44; as they demonstrated a dramatic reduction in proteinuria in four patients while on Interferon &#40;IFN&#41; treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">26</span></a> Moving to the direct acting drugs &#40;DAAs&#41; era several studies demonstrated an association between sustained virological response &#40;SVR&#41; to DAAs and resolution of EHM of HCV as porphyria cutanea tarda&#44;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">27&#44;28</span></a> disturbances in B and T cell homeostasis<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">29</span></a> and some reports indicated a possible improvement in glycemic control&#44; HbA1c and decreased insulin use&#46;<a class="elsevierStyleCrossRefs" href="#bib0445"><span class="elsevierStyleSup">30&#8211;33</span></a> HCV AVT was not only studied in terms of response of existing EHM to treatment&#44; but in terms of risk reduction of developing EHM in the first place&#44; as SVR to IFN has been associated with a reduced risk of MC&#44; GN&#44; porphyria cutanea tarda&#44; NHL&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">34</span></a> and possibly DM&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">35&#8211;38</span></a> Mahale and his research team in their study carried on 160&#44;875 US veterans receiving IFN based therapy and followed up for a median of 5&#46;1 years agreed with the previous studies in terms of risk reductions in MC&#44; GN&#44; porphyria cutanea tarda and DM &#8211; within patients showing SVR as compared to those who didn&#8217;t achieve SVR &#8211; but did not find risk reduction in NHL&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">35</span></a> El Serag et al&#46;&#8217;s study carried on DAA treated patients demonstrated similar results since a significant reduction in the risk of developing MC&#44; GN&#44; lichen planus&#44; and possibly porphyria cutanea tarda was found in patients achieving SVR while there was no such risk reduction for NHL&#46; Yet&#44; El Serag et al&#46;&#8217;s study discorded with Mehale&#39;s as regards the risk of developing DM which was not demonstrated in El Serag&#39;s study&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Clinical and immunological responses</span><p id="par0060" class="elsevierStylePara elsevierViewall">All studies since the IFN era set clinical and immunological responses as the two main parameters for evaluating the response of EHM of HCV to AVT&#44; which could be exemplified as a canvas of clinical response knitted on a background of immunological response framed by SVR&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Saadoun et al&#46; in their early study followed up 72 patients treated with IFN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Ribavirin who achieved an SVR of 58&#37; and complete clinical response &#8211; defined as resolution of vaculitis &#8211; in 62&#46;5&#37;&#44; for 39&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>24&#46;4 months after end of therapy&#46; As for different clinical manifestations&#44; purpura was found to resolve in 86&#37;&#44; arthralgia in 80&#37;&#44; peripheral neuropathy in 68&#37; and renal involvement in 41&#37;&#46; From the immunological aspect&#44; cryoglobulins cleared in 45&#46;8&#37; of patient&#44; cryoglobulin level decreased from a mean of 1&#46;15<span class="elsevierStyleHsp" style=""></span>g&#47;l to 0&#46;27<span class="elsevierStyleHsp" style=""></span>g&#47;l &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; C4 complement level normalized in 70&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; and rheumatoid factor disappeared in 17&#46;8&#37; of patients &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; There was an association between the clearance of cryoglobulins&#44; clearance of RF &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; and normalization of the C4 level &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; Cryoglobulinemia&#44; eGFR&#44; and proteinuria were significantly improved in the SVR group in comparison to the non virological responder group&#46; It is noteworthy that 6 out of 8 virological relapsed 2 months after end of treatment and was associated with cryoglobulinemic vasculitis &#40;CV&#41; relapse as well&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">40</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In the era of DAAs&#44; EHM response to AVT did not seem to differ much despite tremendous increase in virological response&#46; Bonacci and his group<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">41</span></a> on a background of SVR 94&#37; demonstrated 71&#37; complete clinical response of patients with CV which was associated with viral eradication&#44; and 48&#37; immunological response &#8211; defined by the study group as undetectable cryoglobulins and complement and rheumatoid factor normalization &#8211; which was not associated with SVR&#46; Markers of immune activation persisted in 52&#37; of patients&#44; while baseline cryocrit level seemed to be the determinant factor for immunological response as a baseline of &#60;2&#46;7&#37; was the only factor associated with complete immunological response on multivariate analysis&#46; Owing to the findings that&#44; immune activation persistence did not differ significantly between CV patients and those with asymptomatic circulating cryoglobulins &#40;ACC&#41;&#44; only 37&#37; of clinical responders attained immunological improvement&#44; and 73&#37; of immunological responders had clinical improvement&#44; a question may be imposed&#46; Could persistence of immune activation be the trigger of clinical relapse serving as a fire under the straw&#63;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Complete clinical response defined as normalization of vasculitic manifestations and partial response defined as reduction of &#62;50&#37; of vasculitic manifestations were reached in 38&#37; and 22&#37; of symptomatic patients respectively&#44; in Emery et al&#46;&#8217;s retrospective study carried on 18 symptomatic and 65 asymptomatic patients treated with DAA<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>Peg IFN&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">42</span></a> Interestingly&#44; cryoglobulins disappeared in 29&#46;4&#37; symptomatic and 52&#46;9&#37; asymptomatic patients&#44; while SVR did not show significant difference between symptomatic 88&#46;9&#37; and asymptomatic 90&#46;8&#37; patients&#44; which opens a research horizon for exploring possible other players than virological response contributing to immunological response&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Is there a need for adjuvant treatment&#63;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Half of the patients show definite clinical improvements of vasculitis&#44; while renal diseases and lympho-proliferative disorders appear to have a lower remission rate after viral eradication with DAAs and most cases needed immunosuppressive treatments&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">43</span></a> The introduction of the anti CD 20 monoclonal antibody rituximab as an adjuvant to treatment since the IFN era is based on the concept that treatment of HCV EHM involves targeting B cell expansion&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">44</span></a> Rituximab adjunction had shown improved clinical outcomes compared to AVT&#44; in terms of a shorter time to clinical remission &#40;5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4 vs 8&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;7 months&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004&#41;&#44; better renal response rates &#40;80&#46;9&#37; vs 40&#37; of complete response&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;040&#41;&#44; as well as immunological outputs in terms of higher rates of cryoglobulin clearance &#40;68&#46;4&#37; vs 43&#46;6&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and clonal VH1-69<span class="elsevierStyleSup">&#43;</span> B-cell suppression &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">45</span></a> Nevertheless&#44; Sise et al&#46; demonstrated an improvement of eGFR and reduction in proteinuria in patients with active GN who were successfully treated with sofosbuvir plus simeprevir &#8211; showing an SVR of 83&#37; &#8211; particularly in those whose onset of proteinuria was recent&#46; Several patients could decrease immunosuppression&#44; while a single patient was in need to increase immunosuppression and it happened that he had a virologic relapse&#46; A complete immunological response was reached in 44&#37; of patients&#44; with median percent decreasing from 1&#46;5&#37; to 0&#46;5&#37; reaching a nadir at a median of 4&#46;6 months &#40;range 22 days&#8211;13 months&#41; as per protocol&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">46</span></a> This complete response which was found to be permanent in a case report of severe HCV-MCV case treated with ombitasvir&#47;paritaprevir&#47;ritonavir&#44; dasabuvir and ribavirin&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Does response build up by time&#63;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Although a 15-month follow-up study revealed a complete clinical response rate of 72&#46;6&#37;&#44; defined as improvement of all organs involved at baseline and the absence of clinical relapse&#44; which is equivalent to rates in studies of shorter follow-up duration&#46; There was a 22&#46;6&#37; partial response&#44; defined as improvement in some but not all organs involved at baseline&#44; and a 4&#46;8&#37; non-response&#46; Factors associated with partial or no response were severe form of CV and peripheral neuropathy&#46; When breaking down the clinical manifestations&#44; purpura was cleared in 97&#46;2&#37; of patients&#44; renal involvement in 91&#46;5&#37; of patients&#44; arthralgia in 85&#46;7&#37; of patients&#44; and neuropathy in 77&#46;1&#37; of patients&#46; Regarding the immunologic response&#44; 53&#46;1&#37; of patients cleared cryoglobulins in blood samples&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">48</span></a> However&#44; the results of Gragnani et al&#46;&#8217;s study 50 were more meaningful as they tracked the response of EHM to AVT longitudinally rather than obtaining a cross-sectional snapshot&#46; At week 12 post-treatment&#44; they found that 34&#37; were full complete responders clearing all manifestations of vasculitis&#59; 32&#37; were complete responders&#44; showing improvement in all manifestations of vasculitis&#59; 27&#37; were partial responders&#44; experiencing disappearance or improvement of at least half of the manifestations of vasculitis&#46; 7&#37; were non-responders&#44; showing disappearance or improvement of fewer than half of the baseline symptoms&#46; On extending the follow-up to week 24 post-treatment&#44; the percentage of full complete responders increased to 36&#37;&#44; complete responders to 41&#37;&#44; and as a result&#44; partial responders dropped to 24&#37;&#46; Furthermore&#44; the Birmingham Vasculitis Activity Score significantly decreased from 5&#46;41 &#40;&#177;3&#46;53&#41; at baseline to 2&#46;35 &#40;&#177;2&#46;25&#41; at week 4 of treatment&#44; to 1&#46;39 &#40;&#177;1&#46;48&#41; at week 12 post-treatment&#44; and to 1&#46;27 &#40;&#177;1&#46;68&#41; at week 24 post-treatment&#46; It is noteworthy that two patients with partial regression of the symptoms of vasculitis and decrease in the cryocrit level at week 24 after end of therapy developed indolent lymphoma with monoclonal B cell lymphocytosis during the study&#46; By the end of the study&#44; purpura disappeared in 87&#46;5&#37; of patients&#44; arthralgia in 46&#37;&#44; weakness in 56&#37;&#44; peripheral neuropathy in 50&#37;&#44; and renal involvement in 75&#37;&#46; In terms of the immunological response&#44; the mean cryocrit value significantly decreased from 7&#46;2&#37; &#40;&#177;15&#46;4&#37;&#41; at baseline to 2&#46;9&#37; &#40;&#177;7&#46;4&#37;&#41; at 12 weeks post-treatment&#44; and further to 1&#46;8&#37; &#40;&#177;5&#46;1&#37;&#41; at 24 weeks post-treatment&#46; Similarly&#44; a complete immunological response&#44; defined as the disappearance of cryoglobulins&#44; was achieved by 32&#37; of patients at week 12 post-treatment&#44; increasing to 39&#46;5&#37; at week 24 post-treatment&#46; A partial response&#44; defined as a &#60;50&#37; decrease in cryocrit&#44; was achieved by 39&#37; of patients at week 12 post-treatment&#44; but dropped to 34&#37; at week 24 post-treatment&#46; A null response&#44; defined as a &#60;50&#37; decrease in cryocrit&#44; was found in 29&#37; at week 12 post-treatment&#44; decreasing to 26&#46;5&#37; at week 24 post-treatment&#46; RF levels decreased from 131&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>252&#46;9 at baseline to 66&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>91&#46;8 at week 12 post-treatment and to 39&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>29&#46;8 at 24 weeks post-treatment&#46; The findings of this study clearly demonstrate that clinical and immunological responses develop over time &#40;<a class="elsevierStyleCrossRefs" href="#fig0010">Figs&#46; 2 and 3</a>&#41;&#44; which necessitates more longitudinal clinical studies for longer durations to determine whether the elapsed time post-treatment is a factor in relapse or remission&#46; Additionally&#44; it is important to investigate whether there is a time in which the response peaks and whether extending the treatment duration may affect the response rate&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">To sum up a particular pattern for the response of different clinical manifestations of systemic vasculitis secondary to HCV could not be deduced from available clinical studies as demonstrated in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; which could be attributed to lack of head to head studies and the lack of homogeneity in terms of the duration of treatment and types of antiviral medications used&#46; Also&#44; complete clinical response showed variation between different clinical studies as it ranged from 34&#37; to 71&#37;&#44; while immunological response defined as clearance of cryoglobulins was less variable between different studies as it ranged between 32&#37; and 48&#37;&#44; as shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Response of lymphomas to AVT</span><p id="par0095" class="elsevierStylePara elsevierViewall">The strongest worldwide epidemiological association between non-hepatocellular malignancies and HCV was found to be with lymphoproliferative diseases&#44; particularly B-NHL&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">50&#8211;52</span></a> The role of HCV antiviral therapy in the treatment of HCV-associated lymphoproliferative disorders&#44; as well as the positive correlation between virological and hematological responses&#44; has been well established since the IFN era&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">53</span></a> Interestingly&#44; a case of refractory mantle cell lymphoma &#40;MCL&#41; that was resistant to chlorambucil&#44; splenectomy&#44; rituximab&#44; and seven cycles of fludarabine and mitoxantrone achieved complete remission with an undetectable HCV viral load within 1 month of treatment with ribavirin and IFN&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">54</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Successful role of the anti HCV viral therapy in treating HCV associated lymphoproliferative disorders continued through the very first steps of the DAAs era&#44; when DAAs were added to IFN&#46; Michot et al&#46; investigated the role of AVT in 116 HCV-associated B-cell lymphoma patients of different histological types mid zonal lymphoma &#40;MZL&#41;&#44; diffuse large B cell lymphoma &#40;DLBCL&#41;&#44; and other types&#44; 64 of which were treated with IFN<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Ribavirin and only 6 received a protease inhibitor in addition&#46; SVR of 61&#37; was achieved which did not differ between different histological types&#46; Three-year overall survival &#40;OS&#41; and progression free survival were &#40;PFS&#41; 78&#37; &#91;95&#37; CI &#40;63&#8211;88&#41;&#93; and 64&#37; &#91;95&#37; CI &#40;48&#8211;67&#41;&#93; respectively&#44; without differences between cytohistological groups&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">As for hematological response&#44; 78&#37; of MZL patients receiving AVT alone as first-line treatment achieved an overall hematological response&#44; and 57&#37; showed complete response &#40;CR&#41;&#44; defined as the disappearance of all evidence of disease&#46; All responders also showed sustained virological response &#40;SVR&#41;&#44; while the 22&#37; non-responders were non-virological responders as well&#46; Patients treated with AVT-Rituximab combination regimen showed a 62&#46;5&#37; CR&#44; and those treated with chemotherapy<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>rituximab showed a 43&#37; CR&#46; DLBCL patients received front-line immune-chemotherapy with no patients receiving AVT in combination&#44; resulting in an 80&#37; CR&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">55</span></a> It is important to note that despite incorporating a DAA into AVT&#44; the results of this study could not be used to evaluate the role of DAAs in lymphoma treatment&#44; as only 6 out of 70 patients &#40;8&#46;5&#37;&#41; receiving AVT had a DAA in addition&#46; It is also noteworthy that patients with DLBCL did not receive the same front-line treatment as those with MZL&#44; making an accurate comparison between the responses of different types of lymphoma to treatment unattainable&#46; As part of HCV AVT evolution&#44; DAAs were used solely without combination with IFN&#44; and the response of lymphoproliferative disorders did not differ based on the antiviral therapy used&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">56</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">One study demonstrated that SVR 12 was achieved in 98&#37; of patients treated with DAAs&#44; with an overall lymphoproliferative disease response &#40;LDR&#41; of 67&#37;&#44; including 26&#37; complete responders&#46; The highest response was observed among MZL patients&#44; who showed a 73&#37; response&#46; Intriguingly&#44; patients with chronic lymphocytic lymphoma &#40;CLL&#41; and small lymphocytic lymphoma &#40;SLL&#41; showed no response&#46; The 1-year progression-free survival &#40;PFS&#41; and overall survival &#40;OS&#41; rates were as high as 75&#37; &#40;95&#37; confidence interval &#91;CI&#93;&#44; 51&#8211;88&#41; and 98&#37; &#40;95&#37; CI&#44; 86&#8211;100&#41;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">57</span></a> Similar results were later obtained by Frigeni et al&#46; in 2019 in a series of 100 patients&#44; showing an overall response rate &#40;ORR&#41; of 66&#37;&#44; with 23&#37; achieving CR&#46; The response rate was higher in MZL compared to non-MZL &#40;ORR 73&#37; vs&#46; 48&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;021&#59; CR 30&#37; vs&#46; 7&#37;&#44; and partial response &#40;PR&#41; 44&#37; vs&#46; 41&#37;&#44; respectively&#41;&#44; with worse lymphoma response in patients with nodal involvement&#46; No hematological response was documented in patients with CLL&#47;SLL&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">58</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Lin et al&#46; raised concerns as they reported two patients treated with sofosbuvir&#47;ribavirin who cleared the virus but developed de novo aggressive mantle cell lymphoma &#40;MCL&#41; one month after the end of therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">59</span></a> Furthermore&#44; the progression of lymphoma after DAAs has been observed&#44; with six out of 100 patients progressing within three months from the end of DAAs&#46; One of them transformed from splenic MZL to DLBCL&#46; Seven patients progressed between three and 12 months from the start of AVT&#44; and three patients progressed thereafter&#46; Interestingly&#44; progression did not correlate with the pattern of initial response&#44; whether partial or complete&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">58</span></a> This highlights the findings from the aforementioned study by Gragnani et al&#46;&#44; where two patients showing partial clinical response developed indolent lymphoma with monoclonal B cell lymphocytosis despite having a 50&#37; decrease in cryocrit level&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">50</span></a> These findings emphasize the importance of post-DAAs follow-up for early detection of de novo lymphoma or progression of existing ones&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusions</span><p id="par0120" class="elsevierStylePara elsevierViewall">Transitioning from IFN-based therapy to the era of DAAs has yielded favorable results in terms of SVR and side effects&#46; However&#44; the response of EHM does not seem to follow the same pattern and appears to be more complex&#46; Therefore&#44; there is still a need for adjuvant therapy&#44; such as the use of anti-CD20 Rituximab in specific cases&#46; To accurately assess EHM response to AVT&#44; longitudinal studies would be more preferable than cross-sectional ones&#44; as some studies have shown improvement in response over time after cessation of therapy&#44; while others have shown a relapsing pattern&#46; Thus&#44; there is an imperative need for longitudinal clinical studies&#46; Additionally&#44; it would be beneficial if clinical practice guidelines include plans for EHM follow-up post-AVT&#44; addressing response&#44; relapse&#44; and safety concerns&#46; It is noteworthy that reports have pointed to the progression of preexisting lymphoma post-AVT&#46; Finally&#44; confounding factors influencing EHM response to AVT need to be extensively studied as this could refine management and improve overall response rates&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Authors&#8217; contribution</span><p id="par0125" class="elsevierStylePara elsevierViewall">The single author of the article contributed by reviewing the literature and gathering the scientific content and writing the manuscript&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethical consideration</span><p id="par0130" class="elsevierStylePara elsevierViewall">Informed consent is not applicable to this work as it is a review article&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Data availability statement</span><p id="par0135" class="elsevierStylePara elsevierViewall">The data included in this review article could be accessed via the references section&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Funding</span><p id="par0140" class="elsevierStylePara elsevierViewall">There is no financial support for this article&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflict of interest</span><p id="par0145" class="elsevierStylePara elsevierViewall">There is no conflict of interest for this article&#46;</p></span></span>"
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        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
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          "identificador" => "xpalclavsec1788388"
          "palabras" => array:5 [
            0 => "Manifestaciones extrahep&#225;ticas"
            1 => "VHC"
            2 => "Crioglobulinemia"
            3 => "AAD"
            4 => "Vasculitis crioglobulin&#233;mica"
          ]
        ]
      ]
    ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hepatitis C virus &#40;HCV&#41; infection has been associated as up 40&#8211;70&#37; of patients with extrahepatic manifestations &#40;EHM&#41; and 36 different syndromes&#46; These could be attributed to the fact that HCV is lymphotropic&#44; particularly B lymphotropic&#44; and not merely hepatotropic&#44; and could trigger immunological alterations indirectly by exerting a chronic stimulus on the immune system with production of immunoglobulins having rheumatoid activity forming immune complexes and production of cryoglobulins&#46; Cryoglobulinemoa plays a pivotal role in producing most EHM of HCV such as vasculitis&#44; glomerulonephritis&#44; arthritis and neuropathies&#46; Less frequently&#59; while less frequently&#44; the direct viral cytopathic effect could lead to EHMs independent of cryoglobulinemia&#46; The mainstay of treatment of EMH has been antivirals&#44; since interferon era to direct-acting drugs era&#44; with no differences between the two eras&#44; despite the better virological response&#46; Longer evaluation of virological response and clinical investigation with longer follow-ups are necessary&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La infecci&#243;n por el virus hepatitis C &#40;VHC&#41; se ha asociado a 40-70&#37; de los pacientes con alguna manifestaci&#243;n extrahep&#225;tica &#40;MEH&#41; y 36 s&#237;ndromes diferentes&#44; atribuibles a que el VHC es linfotr&#243;pico&#44; particularmente linfotr&#243;pico B&#44; y no simplemente hepatotr&#243;pico&#46; El VHC podr&#237;a desencadenar alteraciones inmunol&#243;gicas al ejercer un est&#237;mulo cr&#243;nico del sistema inmunol&#243;gico con producci&#243;n de inmunoglobulinas con actividad reumatoide y formaci&#243;n de complejos inmunes y crioglobulinas&#46; Estas desempe&#241;an un papel fundamental en la mayor&#237;a de las MEH como vasculitis&#44; glomerulonefritis&#44; artritis y neuropat&#237;as&#44; mientras&#44; menos frecuentemente&#44; el efecto citop&#225;tico viral directo podr&#237;a conducir a MEH independientes de crioglobulinas&#46; El principal tratamiento de las MEH ha sido el antiviral&#44; desde la era del interfer&#243;n hasta la de los f&#225;rmacos de acci&#243;n directa&#44; sin diferencias entre las dos &#233;pocas&#44; a pesar de la mejor respuesta virol&#243;gica&#46; Son necesarias evaluaciones m&#225;s prolongadas de la respuesta virol&#243;gica e investigaci&#243;n cl&#237;nica con seguimientos m&#225;s largos&#46;</p></span>"
      ]
    ]
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        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
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        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Proliferation of B lymphocytes secondary to HCV-CD81 binding&#46; HCV E2 binds CD81 molecule expressed on B-lymphocytes&#44; CD81 forms a costimulatory complex with CD19 and CD21 lowering the threshold required for BCR-mediated B cell proliferation inducing proliferation of na&#239;ve B cells leading to a wide autoantibody and immune-complex production&#46; Ag&#58; antigen&#44; BCR&#58; B cell antigen receptor&#44; E2&#58; envelope of hepatitis C virus&#44; HCV&#58; hepatitis C virus&#44; IG&#58; immunoglobulin&#46;</p>"
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        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Follow up of clinical response post DAA therapy in Gragnani study&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">49</span></a><span class="elsevierStyleItalic">Full complete response</span>&#58; clearance of all manifestations of vasculitis&#44; <span class="elsevierStyleItalic">complete response</span>&#58; improvement of all the manifestations of vasculiti&#44; <span class="elsevierStyleItalic">partial response</span>&#58; disappearance or improvement of at least half of the manifestations of vasculitis&#44; <span class="elsevierStyleItalic">complete immunological response</span>&#58; disappearance of cryoglobulins&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Dynamics of immunological parameters and vasculitis activity in response to DAA therapy Gragnani study&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">49</span></a> Cryocrit is expressed percentage&#44; rheumatoid factor in IU&#47;ml&#46; BVAS&#58; Birmingham vasculitis activity score&#46;</p>"
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            "identificador" => "at1"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">AVT&#58; antiviral therapy&#46;</p>"
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            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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&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">AVT&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">Purpura&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">Arthritis&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">Renal&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">Neuropathy&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Saadoun et al&#46;&#44; 2006<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">40</span></a>&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">IFN&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">86&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">80&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cacoub et al&#46;&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">48</span></a>&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">DAAs&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#46;2&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">85&#46;7&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">91&#46;5&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Graganini et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">49</span></a>&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">DAAs&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">87&#46;5&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">75&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Resolution of different clinical manifestations in different studies&#46;</p>"
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          0 => array:3 [
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">AVT&#58; antiviral therapy&#44; CCR&#58; complete clinical response&#44; CIR&#58; complete immunological response&#44; SVR&#58; sustained virological response&#46;</p>"
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            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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&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">AVT&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">SVR&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">CCR&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">CIR&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">Follow up&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bonacci et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">44</span></a>&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">DAAs&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">48&#37;&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 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Emery et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">45</span></a>&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">DAAs<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Peg IFN&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">90&#46;8&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&#46;8&#37;&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;4&#37;&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 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sise et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">52</span></a>&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">DAAs&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="char" valign="\n
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                  \t\t\t\t">83&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">44&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Gragnani et al&#46;&#44; 2016<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">47</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">DAAs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">100&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">24 weeks&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Cacoub et al&#46;&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">DAAs&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Saadoun et al&#46;&#44; 2006<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">43</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>24 months&nbsp;\t\t\t\t\t\t\n
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      "titulo" => "References"
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Article information

ISSN: 23870206
Original language: English

DOI:10.1016/j.medcle.2023.10.014

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