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Cardiometabolic effects of direct-acting antivirals in patients with hepatitis C
Efectos cardiometabólicos de los antivirales de acción directa en pacientes con hepatitis C
Georgios Neokosmidis, Adonis A. Protopapas
Corresponding author
adoprot@hotmail.com

Corresponding author.
, Dimitrios Stogiannou, Athanasios Filippidis, Konstantinos Tziomalos
First Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
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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">Chronic hepatitis C virus &#40;HCV&#41; infection affects 1&#8211;2&#37; of the world population&#46; HCV is associated with extrahepatic manifestations such as lymphoproliferative processes&#44; autoimmune&#44; cardiovascular&#44; renal and nervous system diseases&#46; Insulin resistance &#40;IR&#41; is reported in up to 70&#37; of cases&#44; and HCV infection has been associated with the development of type 2 diabetes mellitus &#40;T2DM&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> HCV enhances its replication by modulating host cell lipid metabolism&#46; Many lipids are crucial for the virus life cycle&#44; while inhibitors of cholesterol&#47;fatty acids biosynthetic pathways suppress viral replication&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Moreover&#44; recent data have identified HCV infection as a risk factor for cardiovascular disease &#40;CVD&#41;&#44; leading to increased mortality and morbidity&#46; Additionally&#44; atherosclerosis is identified as a result of HCV infection due to chronic HCV infection causing liver and systemic inflammation via increased levels of pro-atherogenic chemokine and cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Another complication of HCV infection is the increased risk of chronic kidney disease &#40;CKD&#41;&#46; HCV and CKD are related for 2 main reasons&#58; first&#44; because patients with CKD can be exposed to the virus through dialysis&#44; and second because HCV infection can induce renal disease&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Finally&#44; elevated uric acid levels represent an independent risk factor for more advanced steatosis in this population&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Direct-acting antivirals &#40;DAAs&#41; have revolutionized the treatment of chronic HCV infection&#46; Accumulating data suggest that these agents exert a wide range of effects on cardiovascular risk factors&#44; which are partly due to HCV eradication&#46; The present review aims to summarize the current evidence on the effects of DAAs on cardiometabolic risk factors and CVD&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Literature search</span><p id="par0015" class="elsevierStylePara elsevierViewall">We conducted a thorough search on the Pubmed&#44; Google Scholar and Cochrane Library databases through February 2021&#46; Search terms included &#8220;DAAs&#8221;&#44; &#8220;Direct Acting-antivirals&#8221;&#44; &#8220;Hepatitis C eradication&#8221;&#44; &#8220;sustained virological response&#8221; &#8220;SVR&#8221; and according to the relevant topic&#58; &#8220;Diabetes mellitus&#8221;&#44; &#8220;DM&#8221;&#44; &#8220;T2DM&#8221;&#44; &#8220;glucose&#8221;&#44; &#8220;insulin resistance&#8221;&#44; &#8220;insulin sensitivity&#8221;&#44; &#8220;CKD&#8221;&#44; &#8220;chronic kidney disease&#8221;&#44; &#8220;renal function&#8221;&#44; &#8220;CVD&#8221;&#44; &#8220;cardiovascular disease&#8221;&#46; &#8220;cardiac&#8221;&#44; &#8220;heart disease&#8221;&#44; &#8220;coronary disease&#8221;&#44; &#8220;atherosclerosis&#8221;&#44; &#8220;hypertension&#8221;&#46; &#8220;lipids&#8221;&#44; &#8220;dyslipidemia&#8221;&#44; &#8220;cholesterol&#8221;&#44; &#8220;triglycerides&#8221;&#44; &#8220;uric acid&#8221;&#44; &#8220;metabolic&#8221;&#44; &#8220;extra-hepatic&#8221;&#46; Furthermore&#44; we examined the references of selected studies and relevant reviews for unidentified studies&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Effect of direct-acting antivirals on the lipid profile</span><p id="par0020" class="elsevierStylePara elsevierViewall">Several studies showed that HCV alters the host lipid metabolism&#46; Processes&#44; such as viral replication&#44; virion circulation and hepatocyte entry&#44; rely on host lipids&#8217; interactions&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;7</span></a> The results of these interactions include hepatic steatosis&#44; hypobetalipoproteinemia and hypocholesterolemia&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Newer DAAs induce sustained virologic response &#40;SVR&#41; in almost all treated patients&#46; HCV clearance after treatment with these agents restores gradually the metabolic disturbances observed during chronic HCV infection&#46; Accordingly&#44; numerous studies reported an increase in total cholesterol &#40;TC&#41; and low-density lipoprotein cholesterol &#40;LDL-C&#41; after treatment with DAAs &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; This increase is rapid in almost all studies and occurs by week 4 of treatment&#44; with slower increases until the end of treatment and at 1 year after treatment&#46; The rapid clearance of HCV by the new DAAs appears to underpin these changes&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Regarding the effects of DAAs on other lipids&#44; serum high-density lipoprotein cholesterol &#40;HDL-C&#41; levels increased in some studies but did not change in others&#46; In contrast&#44; triglyceride &#40;TG&#41; levels did not change in most of the studies&#46; Apolipoprotein &#40;apo&#41; levels were also affected by HCV clearance&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;13</span></a> An increase was found in the levels of Lp&#40;a&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> apoB&#44;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;13</span></a> apoB&#47;apoA1 ratio<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> and apo C2&#44;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;13</span></a> whereas a decrease was reported in the levels of apoA2 and apoE&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10&#44;13</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">HCV genotype&#44; HCV&#47;HIV co-infection and the presence of advanced fibrosis or cirrhosis do not appear to modify the effect of HCV eradication on lipid metabolism&#46; Morales et al reported that the increase in TC and LDL-C levels was irrespective of antiviral therapy or genotype&#44; suggesting that these changes are most likely related to viral clearance than to a direct pharmacological effect&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Townsend et al&#46; showed that HIV co-infection does not substantially modulate the HCV-induced perturbation in serum cholesterol levels&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In a study by Doyle et al&#46;&#44; the presence of cirrhosis did not affect lipid levels during or after treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Finally&#44; many of the cohorts included mixed populations with different HCV genotypes&#44; stages of liver fibrosis and HIV co-infection status but still yielded similar results&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Gene polymorphisms and their impact on lipid metabolism after achieving SVR with DAAs were studied in two clinical trials&#46; Morihara et al&#46; focused on IL28B gene polymorphisms and their effect on lipid levels&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Patients with the IL28B TG&#47;GG genotype experienced larger increases in LDL-C levels after treatment than patients with the TT genotype&#46; In a study by Emmanuel et al&#44; carriers of the IFNL4 &#916;<span class="elsevierStyleItalic">G</span>&#47;TT or &#916;<span class="elsevierStyleItalic">G</span>&#47;&#916;<span class="elsevierStyleItalic">G</span> alleles showed an increase in LDL-C levels after treatment with DAAs whereas carriers of the IFNL4 TT&#47;TT allele showed no change in LDL-C levels&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In liver transplant recipients&#44; treatment of recurrent HCV infection with DAAs reversed the virus&#39;s hypolipidemic effect in a study by Beig et al&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Serum TC and LDL-C levels increased at 41 weeks post-treatment and this increase was independent of dose and trough levels of immunosuppressive therapy and body weight changes&#46; Studies investigating the effects of DAA treatment on the patient&#39;s lipid profile are summarized on <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Effects of DAAs on IR and T2DM</span><p id="par0050" class="elsevierStylePara elsevierViewall">It has been shown that HCV infection induces IR in the liver and peripheral tissues&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Indeed&#44; IR is present in 30&#8211;70&#37; of patients with HCV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Accordingly&#44; patients with HCV infection are 67&#37; more likely to develop T2DM than HCV-negative subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Several studies showed that direct-acting antiviral &#40;DAA&#41; treatment improves insulin sensitivity&#46; In a prospective case-control study &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>133 patients without T2DM&#41;&#44; 76&#46;5&#37; of patients who achieved sustained virological response following treatment with DAA showed improvement in IR&#44; of which 41&#46;2&#37; had normal insulin sensitivity after treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> In a more extensive report in 511 patients with HCV infection &#40;24&#46;7&#37; with T2DM&#41;&#44; SVR following DAA treatment also resulted in improved insulin sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">A number of studies also reported a reduction in fasting plasma glucose &#40;FPG&#41; and HbA<span class="elsevierStyleInf">1c</span> levels after treatment with DAA in patients with HCV infection and T2DM&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> It has also been observed that HbA<span class="elsevierStyleInf">1c</span> levels decrease more in patients who achieve SVR following DAA treatment than those who do not or in those who relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Notably&#44; this improvement in glycemic control appears to be sustained during long-term follow-up&#46; In a study in 122 patients with T2DM&#44; 33&#37; of patients showed improved glycemic control after DAA treatment &#40;defined as a decrease in HbA<span class="elsevierStyleInf">1c</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#37; with no change in antidiabetic treatment or a decrease in the number of antidiabetic medication with no change in HbA<span class="elsevierStyleInf">1c</span>&#41;&#44; which was sustained in 71&#37; of them during a follow-up period of 1&#46;5 years&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> These benefits also appear to be present in special populations&#46; In a retrospective&#44; single-center study in 91 liver transplant recipients with recurrent HCV infection&#44; eradication of HCV infection with DAA treatment was associated with a reduction in HbA<span class="elsevierStyleInf">1c</span> levels and the number of antidiabetic medications&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Treatment with DAA also appears to reduce the risk of new-onset T2DM&#46; In an early study in 82 patients &#40;38&#37; with prediabetes and 17&#37; with T2DM&#41;&#44; DAA treatment resulted in SVR in all patients along with a decrease in glucose and insulin plasma concentration&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Moreover&#44; the prevalence of prediabetes declined to 21&#37; after treatment&#44; particularly in patients who were more insulin resistant as evaluated with the homeostasis model assessment&#46; More importantly&#44; in a recent study in 21&#44;279 patients with HCV infection but without T2DM&#44; treatment with DAA reduced the incidence of T2DM by 53&#37; compared with no treatment or treatment with interferon&#47;ribavirin&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Of note&#44; patients who advanced fibrosis showed more significant reductions in the incidence of T2DM after treatment with DAA&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Effect of direct-acting antivirals on uric acid levels</span><p id="par0070" class="elsevierStylePara elsevierViewall">Few data are available regarding uric acid levels in patients with chronic hepatitis C&#46; Elevated uric acid levels appear to represent an independent risk factor for more advanced steatosis in this population&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In contrast&#44; serum uric acid levels are inversely associated with the severity of fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Limited data also exist on the effects of DAAs on serum uric acid levels&#46; Sato et al&#46; reported a transient increase in serum uric acid levels during combination therapy with sofosbuvir and ribavirin&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Uric acid levels reached a maximum on week 1 of treatment and then gradually dropped to pre-treatment levels at the end of treatment&#46; A number of possible pathogenetic mechanisms were proposed&#44; such as potential renal toxicity of SOF or RBV&#44; a rapid disruption of HCV RNA that might affect purine metabolism&#44; dose-dependent hemolytic anemia caused by RBV&#44; and possible interactions between SOF and xanthine oxidoreductase &#40;XOR&#41; or breast cancer resistance protein &#40;BCRP&#41;&#46; In contrast&#44; in a prospective cohort study by Jang et al&#46; in 213 patients with chronic HCV infection&#44; a decrease in serum uric acid levels and the prevalence of hyperuricemia was observed after treatment with DAAs&#44; but only in patients with a fibrosis-4 index &#40;FIB-4&#41;<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>6&#46;5&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Effects of treatment with DAAs on renal function</span><p id="par0080" class="elsevierStylePara elsevierViewall">HCV has a detrimental effect on kidney function<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> and CKD is more prevalent in patients with chronic HCV infection than in the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Accordingly&#44; and because of the high HCV prevalence in patients undergoing dialysis&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> many studies investigated the effects of antiviral therapy on renal function in patients with chronic HCV infection&#46; Studies that evaluated IFN-based treatment demonstrated improvements in glomerular filtration rate &#40;GFR&#41; in patients achieving SVR&#44; even in special populations such as patients undergoing hemodialysis or in those who had received liver transplantation&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#8211;33</span></a> More recently&#44; 2 studies evaluated both IFN-based and IFN-free combinations&#46; Park et al evaluated the effect of antiviral treatment on CKD development in 55&#44;818 patients with HCV&#44; among which 11&#44;828 patients received therapy&#44; with 4628 receiving all-oral DAA treatment and the rest receiving IFN-based treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> While treatment was associated with a lower risk for CKD &#40;hazard ratio &#40;HR&#41; 0&#46;70&#41;&#44; this benefit was observed only in patients who received IFN-based therapy&#46; Perez de Jose et al evaluated renal outcomes in 139 patients with HCV-associated mixed cryoglobulinemia&#44; of whom 100 received DAA therapy&#44; 24 IFN-based therapy and 15 were untreated&#44; during a follow-up period of 138 months&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Patients receiving DAAs had significantly less risk &#40;HR 0&#46;10&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; of receiving renal replacement therapy &#40;RRT&#41; or experiencing a two-fold increase in baseline serum creatinine levels&#46; Additionally&#44; a reduction in albuminuria was observed in patients treated with DAAs&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Several studies evaluated the effects of DAAs on GFR&#46; Mehta et al analyzed 3319 patients treated with the combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir &#40;3D&#41; from 3 different trials and reported that GFR decreased in patients with normal renal function &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and did not change in patients with CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> In another study in 13&#44;663 patients receiving SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ledipasvir &#40;LED&#41; and 3961 patients receiving 3D&#44; 30&#8211;38&#37; of patients showed a decline of &#62;10<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> in GFR at 12 weeks after treatment&#59; in contrast&#44; among patients with stage 4 and 5 CKD&#44; only 0&#8211;6&#37; showed a decline in GFR&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> In a study by Chiu et al in a cohort of 1536 HCV patients treated with 4 different DAAs regimens&#44; GFR decreased at 48 weeks post-treatment compared with baseline &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Finally&#44; a study by Sise et al&#46; evaluated patients 3 years after DAA treatment a reported a reduction in the rate of GFR decline in patients with GFR<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; and a faster decline in patients with GFR<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Many studies evaluated SOF-based regimens&#8217; effect on renal function because SOF has a primarily renal elimination and is not recommended in patients with GFR<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Aby et al reported that among patients treated with SOF-based regimens &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>523&#41;&#44; those who achieved SVR had a similar change in GFR with untreated patients&#46; In contrast&#44; patients not achieving SVR had a significant deterioration in GFR &#40;mean 11<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Similarly&#44; in 5 studies evaluating SOF-based treatments in patients with concomitant HIV infection&#44; GFR did not change after treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;42</span></a> Furthermore&#44; in a study by Liu et al in 308 patients treated with SOF-based and 173 treated with SOF-free regimens&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> the latter showed an improvement in GFR both during and after treatment&#44; whereas those treated with SOF-based regimens experienced a reduction in GFR during therapy and a smaller improvement post-therapy&#46; In contrast&#44; Coppola et al&#46; reported that patients treated with SOF-based regimens had an increase in GFR post-treatment&#44; whereas patients on SOF-free regimens had no change in GFR&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Notably&#44; patients with CKD or cirrhosis at baseline experienced an increase in GFR&#44; whereas those without CKD or cirrhosis showed no change in GFR&#46; Conversely&#44; in a study by Chen et al&#44; patients with cirrhosis undergoing treatment with SOF-based regimens showed decreased GFR&#44; whereas those without cirrhosis did not&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">A number of studies evaluated the effects of DAAs on renal function in patients with HCV infection who had undergone liver transplantation&#46; Notably&#44; Beig et al reported an increase in GFR in 97 patients receiving DAA therapy &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Studies evaluating the effects of DAA therapy on renal function are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Effects of treatment with DAAs on cardiac function</span><p id="par0100" class="elsevierStylePara elsevierViewall">Conflicting data have been reported regarding the effects of DAAs on cardiac function&#46; Mazzitelli et al&#46; evaluated global longitudinal strain &#40;GLS&#41; and ejection fraction &#40;EF&#41; in 82 patients before and 24 weeks after treatment with SOF-based DAAs&#46; While EF did not change&#44; GLS worsened at the end of the follow-up period &#40;mean GLS increase 0&#46;07&#47;month&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> In contrast&#44; another study reported decreased left and right atrial and right ventricular volume at 6 months after the end of therapy with DAAs in 56 non-obese&#44; non-diabetic patients with low fibrosis score&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Impact of DAA treatment on subclinical atherosclerosis</span><p id="par0105" class="elsevierStylePara elsevierViewall">Chronic HCV infection is associated with an increased prevalence of subclinical atherosclerosis&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Recently&#44; a number of studies evaluated the effects of DAA treatment on subclinical atherosclerosis&#46; In a multicenter study in 182 consecutive HCV patients with advanced fibrosis &#40;F3&#41; or compensated cirrhosis &#40;66&#37; of patients&#41;&#44; carotid intima-media thickness and the proportion of patients with carotid thickening decreased 9&#8211;12 months after the end of DAA therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> In another recent study in 114 patients&#44; treatment with DAAs improved endothelial function and reduced the ankle-brachial index&#44; a marker of peripheral arterial disease&#44; in patients with endothelial dysfunction and subclinical atherosclerosis at baseline&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> In contrast to these beneficial effects of DAAs on subclinical atherosclerosis&#44; a prospective study in 102 patients treated with DAAs reported an increase in arterial stiffness&#44; evaluated with the augmentation index and central blood pressure&#44; in patients with advanced fibrosis after SVR but not in those with no or mild fibrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Effects of DAAs on cardiovascular events</span><p id="par0110" class="elsevierStylePara elsevierViewall">Chronic hepatitis C appears to be associated with increased cardiovascular morbidity&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;52</span></a> A small number of early studies suggested that IFN-based therapies might improve cardiovascular outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#44;53</span></a> More recently&#44; a number of studies compared the effects of IFN-based and IFN-free regimens on cardiovascular events&#46; Nahon et al&#46; evaluated the risk of major adverse cardiovascular events &#40;MACE&#41;&#44; including stroke&#44; ischemic heart disease&#44; cardiovascular death&#44; cardiac arrest&#44; and heart failure in 1323 patients with cirrhosis after HCV treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> One-fourth of the patients received IFN-free combinations&#46; SVR was observed in 50&#46;5&#37; of patients and was associated with a lower risk for cardiovascular events &#40;HR 0&#46;49&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; and MACE &#40;HR 0&#46;53&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; after a mean follow-up of 58 months&#46; In a more recent analysis from the same group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>878&#41;&#44; SVR was again independently associated with a lower risk for MACE &#40;HR 0&#46;35&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> Another study investigating the effect of HCV treatment on the incidence of cardiovascular events was undertaken using a large database in the US and by matching patients treated with both IFN-free &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#44;467&#41; and IFN-based &#40;4436&#41; regimens with untreated controls&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Both treatment with DAAs and with IFN-based regimens were associated with reduced incidence of cardiovascular events &#40;HR 0&#46;57 and HR 0&#46;78 respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41;&#44; irrespective of SVR&#46; Interestingly&#44; in a sub-analysis&#44; patients treated with DAAs had a lower incidence of cardiovascular events than patients treated with IFN-based regimens &#40;HR 0&#46;8&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Adinolfi et al&#46; prospectively evaluated 1668 patients treated with DAAs and 486 untreated patients as controls<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> and reported after a median follow-up of 28 months that SVR was associated with reduced risk of cardiovascular events &#40;relative risk &#40;RR&#41; 0&#46;38&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Another study compared 13&#44;125 patients treated with DAAs and 96&#44;252 untreated patients followed-up for 350 days and reported a lower incidence rate of cardiac &#40;RR 0&#46;71&#41; and cerebrovascular &#40;RR 0&#46;74&#41; events in the former&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Finally&#44; one study addressed the effect of HCV treatment on estimated cardiovascular risk as assessed by the Framingham study risk equation in 237 patients with HIV&#47;HCV co-infection<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> receiving mainly IFN-based treatment &#40;90&#37;&#41;&#46; Patients who achieved SVR showed a decrease in estimated cardiovascular risk &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; while patients who did not achieve SVR showed no change in risk &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;433&#41;&#46; Studies evaluating the effects of DAA therapy on cardiovascular eventsare summarized in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclusions</span><p id="par0115" class="elsevierStylePara elsevierViewall">Nowadays&#44; DAA&#39;s are the cornerstone treatment of HCV&#44; effectively minimizing liver-related outcomes in patients achieving SVR and spearheading the World Health organizations&#8217; plan for the global eradication of HCV by 2030&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> Additionally&#44; HCV eradication&#39;s effects seem to expand to extrahepatic processes and diseases&#46; Increased insulin resistance is a well-documented effect of HCV&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> leading to significant benefits in insulin sensitivity and T2DM incidence or control in patients treated with DAAs&#46; Additionally&#44; data suggest that treatment with DAAs reduces the risk of CVD and stroke incidence in patients with HCV infection compared with untreated patients&#46; Combined effects on atherosclerosis&#44; insulin resistance and oxidative stress are proposed as the mechanisms behind this outcome&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Existing studies appear conflicting regarding the long-term effect of DAAs on renal function&#46; However&#44; most studies point towards a succinct renal function trajectory during and after DAAs therapy&#44; with GFR trending downwards during therapy and upwards after the end of treatment&#46; In conjunction with the limited length of follow-up of most studies &#40;due to the relatively recent emergence of DAAs&#41;&#44; this fact may indicate long-term renal function improvement as a consequence of DAAs therapy&#46; Furthermore&#44; given that chronic HCV infection is associated with increased cardiovascular risk&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> the increase in LDL-C levels after achieving SVR with the new DAAs and its associated cardiovascular implications are a reason of concern&#46; Accordingly&#44; monitoring of lipid levels and&#44; when appropriate&#44; administration of lipid-lowering agents are recommended&#46; Finally&#44; although an elevated uric acid may represent a risk factor for advanced steatosis in this population&#44; more studies are needed to ensure this hypothesis&#46; To sum up&#44; the massive eradication campaigns inspired by the emergence of DAAs have started to uncover the magnitude of extrahepatic effects of HCV and its subsequent eradication&#46; DAA treatment&#39;s effects seem to be mostly beneficial&#44; with a few exceptions&#44; such as the effects on lipid metabolism&#46; Nevertheless&#44; as we move further away from the beginning of the DAA era&#44; these effects will be more pronounced and easier to quantify&#46; Therefore&#44; in the next few years&#44; more studies are expected&#44; which would provide definitive answers regarding the effect of DAAs treatment on significant cardiometabolic processes&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hepatitis C virus &#40;HCV&#41; has long been associated with several extrahepatic manifestations&#44; including increased cardiovascular risk&#46; The emergence of direct-acting antivirals &#40;DAAs&#41; has allowed us to evaluate the potential reversal of these manifestations after successful treatment&#46; Therefore&#44; many studies have provided significant takeaways regarding the positive effect of DAAs therapy on insulin resistance&#44; type 2 diabetes mellitus&#44; cardiovascular disease and atherosclerosis&#46; In contrast&#44; studies have shown detrimental effects on lipid metabolism and indeterminate results regarding renal function and uric acid metabolism&#46; Nevertheless&#44; as more and more patients achieve sustained virological response&#44; the effects of HCV eradication on cardiometabolic processes will be extensively studied&#44; allowing more reliable conclusions on the extent of extrahepatic outcomes&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El virus de la hepatitis C &#40;VHC&#41; se ha asociado durante mucho tiempo a varias manifestaciones extrahep&#225;ticas&#44; entre ellas el aumento del riesgo cardiovascular&#46; La aparici&#243;n de los antivirales de acci&#243;n directa &#40;AAD&#41; ha permitido evaluar la posible reversi&#243;n de estas manifestaciones tras un tratamiento exitoso&#46; As&#237;&#44; muchos estudios han aportado datos significativos sobre el efecto positivo del tratamiento con AAD en la resistencia a la insulina&#44; la diabetes mellitus de tipo 2&#44; la enfermedad cardiovascular y la aterosclerosis&#46; Por el contrario&#44; los estudios han mostrado efectos perjudiciales sobre el metabolismo de los l&#237;pidos y resultados indeterminados respecto a la funci&#243;n renal y el metabolismo del &#225;cido &#250;rico&#46; No obstante&#44; a medida que un mayor n&#250;mero de pacientes logre una respuesta virol&#243;gica sostenida&#44; se estudiar&#225;n ampliamente los efectos de la erradicaci&#243;n del VHC sobre los procesos cardiometab&#243;licos&#44; lo que permitir&#225; obtener conclusiones m&#225;s fiables sobre el alcance de los resultados extrahep&#225;ticos&#46;</p></span>"
      ]
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      0 => array:8 [
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        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">SOF&#58; Sofosbuvir&#44; RBV&#58; Ribavirin&#44; DCV&#58; Daclatasvir&#44; ASV&#58; Asunaprevir&#44; LDV&#58; Ledipasvir&#44; DAAs&#58; Direct-acting antivirals&#44; PEG-IFN&#58; Pegylated interferon&#44; PrOD&#58; Paritaprevir&#47;Ritonavir&#47;Ombitasvir&#47;Dasabuvir&#44; OBV&#47;PTV&#47;r&#58; Ombitasvir&#47;Paritaprevir&#47;Ritonavir&#44; <span class="elsevierStyleItalic">&#916;</span>&#58; Change &#40;&#37;&#41;&#44; CHOL&#58; Total cholesterol&#44; TRIG&#58; Triglycerides&#44; NS&#58; non-significant&#46;</p>"
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                  \t\t\t\t">Morales<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SOF regimen&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#43; 28&#46;1&#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">&#43; 10&#46;6&#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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&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
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                  \t\t\t\t">Morihara<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">121&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">DCV&#47;ASV for 24 weeks - &#40;OBV&#47;PTV&#47;r for 12 weeks &#8211; SOF&#47;LDV for 12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43; 11&#46;9&#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">&#43; 24&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43; 7&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NS&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">Emmanuel<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">301&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43; 24&#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">NS&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">&#8722; 13&#46;4&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">SVR&#58; Sustained viral response&#44; CKD&#58; Chronic kidney disease&#44; DAA&#58; Direct acting antiviral&#44; IFN&#58; Interferon&#44; PrOD&#58; Paritaprevir&#47;Ritonavir&#47;Ombitasvir&#47;Dasabuvir&#44; RBV&#58; Ribavirin&#44; SOF&#58; Sofosbuvir&#44; GFR&#58; Glomerular filtration rate&#44; LDV&#58; Ledipasvir&#44; HIV&#58; Human Immunodeficiency virus&#44; HCV&#58; Hepatitis C virus&#44; LT&#58; Liver transplantation&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "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&#47;year type&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">Mean follow-up&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">Population&#47;regimens&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">Significant outcomes&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">Park<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&#47;2018Retrospective&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">First CKD diagnosis&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&#58; 4628IFN-based&#58; 7200Untreated&#58; 43&#44;990&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">&#63;&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">Treatment associated with reduced incidence of CKD&#44; only in IFN-based group&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">Perez de Jose<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a>&#47;2020Retrospective&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">138 months&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&#58; 100IFN-based&#58; 24Untreated&#58; 15&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&#58; 98&#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">DAAs treatment associated with reduced risk of renal events &#40;dialysis&#44; 2&#215; creatinine elevation&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\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">Mehta<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a>&#47;2020Phase 3 trials&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">52 weeks post-treatment&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">3319 patients under PrOD<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>RBV&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">95&#8211;97&#46;6&#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">Significant GFR decrease in CKD stage 1 patients&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">Butt<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a>&#47;2018Retrospective&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 post-treatment&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">PrOD<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>RBV&#58; 3961SOF-LDV<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>RBV&#58; 13663&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">98&#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">GFR&#58; Decline<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> in 30&#8211;38&#37; of patients&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">Chiu<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a>&#47;2020Retrospective&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">Three years pre- and post-treatment&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&#58; 1536Cirrhosis&#58; 59&#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">&#63;&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">Treatment associated with significant GFR decrease&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<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#47;2020Retrospective&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">6 months post treatment&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&#58; 1178&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">93&#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">Increase decline of GFR in patients with GFR<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>60 compared to patients with &#60;60&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">Aby<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&#47;2017Retrospective&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 post-treatment&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">SOF-based&#58; 523Untreated&#58; 439Cirrhosis&#58; 49&#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">93&#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">GFR&#58; No difference between SVR and untreated patients&#44; significant decline in non-SVRpatients&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">Soeiro<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&#47;2018Prospective&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 post-treatment&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">HIV&#47;HCV &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>273&#41;Sof-based&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">99&#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">GFR&#58; decrease during treatment&#44; recovery to baseline levels at week 12 post-treatment&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">Taramasso<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a>&#47;2017Prospective&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 post-treatment&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">HIV&#47;HCV &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>79&#41;Sof-based&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">88&#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">Insignificant change in GFR during treatment and follow-up&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">Liu<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a>&#47;2020Retrospective&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">24 weeks post-treatment&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">SOF-based&#58; 308SOF-free&#58; 173&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">98&#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">SOF-free&#58; on- and off-therapy GFR improvementSOF-based&#58; on therapy worsening&#44; off-therapy improvement&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">Coppola<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a>&#47;2019Prospective&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 post-treatment&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">SOF-based&#58; 280SOF-free&#58; 123Cirrhosis&#58; 36&#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">98&#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">GFR improvement in patients with cirrhosis&#44; CKD and treated with SOF-based regimens&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">Chen<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a>&#47;2017Retrospective&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">24 weeks post-treatment&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">SOF-based&#58; 43Cirrhosis&#58; 42&#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">93&#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">Cirrhosis&#58; significant GFR decrease&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">Beig<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#47;2018Retrospective&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">24 weeks post-treatment&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">LT patients &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>91&#41;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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96&#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">Treatment associated with significant GFR increase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Studies investigating the effect of treatment with DAAs on renal outcomes&#46;</p>"
        ]
      ]
      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">SVR&#58; Sustained viral response&#44; CVD&#58; Cardiovascular disease&#44; MACE&#58; Major adverse cardiovascular events&#44; DAA&#58; Direct acting antiviral&#44; IFN&#58; Interferon&#44; SOF&#58; Sofosbuvir&#44; HIV&#58; Human Immunodeficiency virus&#44; HCV&#58; Hepatitis C virus&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "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&#47;Year Type&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">Mean follow-up&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">Population&#47; Regimens&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">Significant Outcomes&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></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">Nahon&#91;54&#93;&#47;2017Retrospective&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">58&#46;2 months&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">CirrhosisIFN-free&#58; 328IFN-based&#58; 995&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">50&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SVR associated with reduced risk of CVD and MACE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-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">Singer&#91;58&#93;&#47;2017Retrospective&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">350 days&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">Untreated&#58; 96252DAAs&#58; 13125&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">&#63;&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">Treatment associated with reduced risk of cardiac and cerebrovascular events&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-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">Carrero&#91;59&#93;&#47;2020Prospective&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96 weeks post-treatment&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">HIV&#47;HCV&#58; 237IFN-free&#58; 89&#37;IFN-based&#58; 11&#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">62&#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">Decrease of CVD risk score only in patients with SVR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-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">Butt&#91;56&#93;&#47;2019Retrospective&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">First CVD event&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&#58; 12667IFN-based&#58; 4436Untreated&#58; 17103&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">76&#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">Treatment vs no treatmentDAAs vs 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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lower risk of CVD events&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">Adinolfi&#91;57&#93;&#47;2020Prospective&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">28 months&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&#58; 1668Untreated&#58; 486&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">98&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Treatment&#47;SVR&#58; Lower risk for CVD events&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Studies investigating the effect of treatment with DAAs on cardiac outcomes&#46;</p>"
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    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:60 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "metabolic syndrome&#44; and inflammatory markers&#58; results from the Third National Health and Nutrition Examination Survey &#91;NHANES III&#93;"
                      "autores" => array:1 [
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ISSN: 24443824
Original language: English
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