Treatment of hepatitis C virus with direct-acting antivirals: Practical aspects and current situation

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Vivancos, A. Moreno, C. Quereda" "autores" => array:3 [ 0 => array:2 [ "nombre" => "M.J." "apellidos" => "Vivancos" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Moreno" ] 2 => array:4 [ "nombre" => "C." "apellidos" => "Quereda" "email" => array:1 [ 0 => "carmen.quereda@salud.madrid.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Enfermedades Infecciosas, Hospital Ramón y Cajal, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento del virus de la hepatitis C con antivirales de acción directa: Aspectos prácticos y situación actual" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1528 "Ancho" => 2353 "Tamanyo" => 232489 ] ] "descripcion" => array:1 [ "en" => "Replication cycle of hepatitis C virus and therapeutic targets." ] ] ] "textoCompleto" => "BackgroundThe hepatitis C virus (HCV) affects more than 170 million individuals worldwide.<a class="elsevierStyleCrossRefs" href="#bib0185">1,2</a> HCV is the main cause of hepatic cirrhosis and hepatocarcinoma and is the most common indication for liver transplantation.<a class="elsevierStyleCrossRefs" href="#bib0195">3,4</a> Half a million individuals die every year from HCV-related liver disease.<a class="elsevierStyleCrossRef" href="#bib0205">5</a>The HCV genome does not integrate with that of the host, and therefore its replication can be definitively inhibited, curing the infection. It has been shown that the sustained viral response (SVR) achieved with HCV treatment improves the histology and progression of liver disease.<a class="elsevierStyleCrossRefs" href="#bib0210">6,7</a> Chronic liver disease due to HCV began to be treated in 1991 with subcutaneous interferon alpha in monotherapy. The efficacy of this treatment regimen was low, and tolerance was poor. In 1998, ribavirin was included in the treatment, improving the SVR rates but without significantly increasing the adverse effects of interferon. In 2000, conventional interferon alpha was replaced by pegylated interferon (alpha 2a or alpha 2b), improving the response and tolerance. Neither interferon nor ribavirin have a direct antiviral effect against HCV but instead act by an immune-mediated mechanism.Telaprevir and boceprevir, the first direct-acting antivirals (DAAs) employed for treating chronic HCV infection, were marketed in 2011. Their mechanism of action inhibits the HCV protease (PI). These DAAs were approved for treatment in combination with pegylated interferon and ribavirin.<a class="elsevierStyleCrossRef" href="#bib0220">8</a> Although this treatment regimen achieved a significant increase in the percentage of patients with SVR, the regimen had significant limitations: it was only effective for patients with genotype 1, the treatment regimens were complex, the number of pills were high, the patients had intolerance or were contraindicated for interferon, and the efficacy in subgroups with predictors of poor response continued to be low.In 2013, new DAAs began to appear, which inhibited some of the steps in the virus replication cycle. Using combinations of these drugs, highly effective, short and well-tolerated interferon-free treatment regimens have been achieved, which have revolutionized HCV treatment, even for patients with advanced stages of cirrhosis.<a class="elsevierStyleCrossRefs" href="#bib0225">9–11</a>Replication cycle of the hepatitis C virus. Therapeutic targetsHCV is an RNA virus of the Flaviviridae family. To date, 6 genotypes have been described (1a/1b, 2, 3, 4, 5 and 6). In Europe and the United States, the most common genotype is 1, followed by genotypes 3 and 4.<a class="elsevierStyleCrossRefs" href="#bib0185">1,2</a> As with the human immunodeficiency virus (HIV), HCV has a high viral replication rate and a low error correction capability due to its polymerase RNA. For patients with chronic infection, these characteristics promote a considerable diversity of viral quasispecies. However, HCV does not integrate with the infected host's genome, and HCV's entire cycle is performed in the cytoplasm. Treatments that effectively block its replication can therefore eradicate the infection. The replication cycle of HCV offers numerous therapeutic targets (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The HCV virion enters the cells by endocytosis through a receptor. HCV then releases its genome, which is directed to the cell's endoplasmic reticulum, where it forms a polyprotein of approximately 3011 amino acids through a translation process. The HCV protease, encoded by the NS3/4A genome region, is responsible (along with other cell proteases) for completing the hydrolysis of this polyprotein, which is segmented into 3 structural and 7 nonstructural proteins.<a class="elsevierStyleCrossRef" href="#bib0240">12</a> Inhibitors of this viral protease have been designed that bind to the viral's active center, blocking its action and viral replication. The composed proteins and the viral RNA interact with the NS5A protein, which is associated with the membrane and is phosphorylated by a cell serine-kinase. The NS5A protein has no known enzymatic function but is essential for RNA replication and the assembly of new viral particles.<a class="elsevierStyleCrossRef" href="#bib0240">12</a> NS5A inhibitors block the binding with proteins and inhibit the relationship between the NS5A protein and the locations of HCV intracellular replication.Moreover, a nonstructural RNA-dependent RNA polymerase protein (NS5B) is also involved in viral RNA replication, which produces a negative-strand RNA and serves as a mold for manufacturing positive-strand RNA. The NS5B nucleoside analogues incorporate in the RNA and block the chain, inhibiting HCV replication through the binding to the enzyme's catalytic site (conserved). This area is common in all genotypes; the drugs that act on this target are therefore active against all genotypes (pangenotypics). In contrast, non-nucleoside NS5B inhibitors are noncompetitive inhibitors, which block RNA synthesis before the start of the chain and are more dependent on the viral genotype.<a class="elsevierStyleCrossRef" href="#bib0240">12</a> The newly manufactured viral genomes can once again be replicated and translated or packaged to form new viral particles. These new viral particles are released by exocytosis, completing the cycle.<a class="elsevierStyleCrossRef" href="#bib0245">13</a>Direct-acting antivirals. Classification according to their mechanism of actionThe currently available DAAs are classified according to the target of the HCV replication cycle on which they act:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-Protease inhibitors (PI) NS3/4A.</li><li class="elsevierStyleListItem" id="lsti0010">-NS5A protein inhibitors.</li><li class="elsevierStyleListItem" id="lsti0015">-NS5B polymerase inhibitors, which in turn can be nucleoside analogues and non-nucleoside analogues.</li></ul>NS3/4A protease inhibitorsThese agents act by inhibiting the HCV protease NS3/4A and thereby the replication of the virus. The drugs belonging to this family are named with the suffix “previr”. Telaprevir and boceprevir were the first to be used and are therefore considered first-generation HCV PIs.<a class="elsevierStyleCrossRefs" href="#bib0250">14,15</a> Due to their above-mentioned limitations, the drugs were replaced by other PIs.The second and third-generation PIs, which have been marketed, are polygenotypic drugs with activity against the HCV genotypes 1, 2 and 4 (although the drugs are not used for HCV genotype 2). However, the drugs have no activity against genotype 3, and there is little experience with genotypes 5 to 7. Within genotype 1, the drugs are more active against subtype 1b. The first-generation PIs have greater potency, safety, tolerance and a longer half-life, which allow them to be administered once a day with fewer drug interactions. Nevertheless, potential interactions should be checked, and the patient should be instructed not to take any new drug without a previous consultation.<a class="elsevierStyleCrossRef" href="#bib0260">16</a> Although resistant mutations can be generated in patients treated with these drugs, the genetic barrier of these drugs to resistance is much greater than that of first-generation PIs. The resistance mutations generated during treatment with some of these drugs does not jeopardize the response with other drugs of the same family.The currently approved HCV PIs in Europe and the US are simeprevir, paritaprevir (which are administered boosted with ritonavir) and grazoprevir. Glecaprevir (AbbVie)<a class="elsevierStyleCrossRef" href="#bib0265">17</a> and voxilaprevir (Gilead)<a class="elsevierStyleCrossRef" href="#bib0270">18</a> are 2 potent new-generation pangenotypic PIs, with activity against genotype 3 and are currently in advanced phases of research.NS5A inhibitorsThese drugs act by inhibiting the NS5A replication complex. The drugs that belong to this family are pangenotypic and are named with the suffix “asvir”. As with the PIs, the drugs have greater activity within genotype 1 against subtype 1b. The drugs are potent, well-tolerated and have pharmacokinetics that allows for administration once a day. Their adverse effects are generally mild. Although these drugs generally have fewer interactions than PIs, the interactions should always be considered when these drugs are used concomitantly with other drugs.<a class="elsevierStyleCrossRef" href="#bib0260">16</a>The currently approved NS5A inhibitors in Europe and the US are daclatasvir, ombitasvir, ledipasvir, velpatasvir and elbasvir. All but the first are coformulated with another DAA. Pibrentasvir is a new NS5A inhibitor, which will be used coformulated with glecaprevir (AbbVie).<a class="elsevierStyleCrossRef" href="#bib0265">17</a> The drug is still being researched, but the results from phase III studies have been presented, with excellent results in all genotypes, without needing to add ribavirin.<a class="elsevierStyleCrossRef" href="#bib0265">17</a>The genetic barrier of this family of drugs is moderate. Resistance mutations are frequently selected in patients who fail a treatment regimen that includes one of these drugs. This possibility is lower with more modern NS5A inhibitors (velpatasvir, elbasvir and pibrentasvir).<a class="elsevierStyleCrossRef" href="#bib0275">19</a>NS5B polymerase inhibitorsThese drugs act by inhibiting the HCV RNA polymerase NS5B. Drugs belonging to this family are named with the suffix “buvir”. There are 2 types of these drugs: nucleoside analogues and non-nucleoside analogues. We currently only have sofosbuvir in the first group and dasabuvir in the second.The general characteristics of NS5B nucleoside analogue polymerase inhibitors are as follows: (1) high antiviral potency; (2) high barrier to resistance; (3) pangenotypics; (4) easy posology, and (5) few adverse effects and interactions. These characteristics make the drugs attractive as components of any treatment regimen. In contrast, NS5B non-nucleoside analogue polymerase inhibitors, although safe and well-tolerated, have low antiviral potency, limited activity against genotype 1 and a low genetic barrier, which frequently results in the appearance of strains with resistance mutations in the therapeutic failures.Characteristics of the available drugs for HCV treatmentDrugs without coformulationSimeprevir (Olysio®, Janssen)This is a second-generation HCV PI that is effective in patients with genotypes 1 and 4. Dosages of 150mg a day are employed, in 12 to 24-week regimens. There is experience with the use of simeprevir combined with pegylated interferon and ribavirin,<a class="elsevierStyleCrossRef" href="#bib0280">20</a> with sofosbuvir<a class="elsevierStyleCrossRef" href="#bib0285">21</a> and with daclatasvir.<a class="elsevierStyleCrossRef" href="#bib0290">22</a> When combined with sofosbuvir, simeprevir has shown SVR rates of more than 80%; the combination with ribavirin does not improve the results.<a class="elsevierStyleCrossRef" href="#bib0295">23</a> When combined with daclatasvir, the results are unsatisfactory, and there is very little experience with this combination. The response rates with simeprevir are lower in patients with genotype 1 and the Q80K mutation, especially in regimens in which it is combined with interferon and ribavirin.<a class="elsevierStyleCrossRef" href="#bib0280">20</a> The drug is not recommended for patients who have previously failed regimens with an HCV PI.<a class="elsevierStyleCrossRef" href="#bib0300">24</a>Simeprevir is a very well-tolerated drug, with generally mild adverse effects. The most common adverse effects include skin rashes, photosensitivity and increased transaminase and bilirubin levels.<a class="elsevierStyleCrossRef" href="#bib0305">25</a> The drug is not recommended for patients with advanced liver disease (Child–Pugh classes B and C), because the disease can increase its serum levels and its toxicity. Interactions can occur with other cytochrome P450 3A inducers and inhibitors.Due to its lower potency, potential drug interactions and lack of coformulation with other agents against HCV, simeprevir is rarely used and has been displaced by other options. The drug can still have a certain usefulness for the few patients for whom other regimens with DAA fail.<a class="elsevierStyleCrossRef" href="#bib0300">24</a>Daclatasvir (Daklinza®, BMS)This drug is a first-generation NS5A protein inhibitor, active against genotypes 1 to 6. Dosages of 60mg a day are employed, in 12 to 24-week regimens. The dose must be reduced to 30mg when used with atazanavir-ritonavir, azole or clarithromycin. If used along with efavirenz, etravirine or dexamethasone, the dosage should be increased to 90mg a day.<a class="elsevierStyleCrossRef" href="#bib0310">26</a> Although there is experience with the drug combined with various DAAs, the most studied and effective regimen is the combination with sofosbuvir, with or without ribavirin. Despite its safety and efficacy, the regimen is not a first-choice regimen, because there are other more comfortable options with better cost-efficiency.Sofosbuvir (Sovaldi®, Gilead)This is an NS5B polymerase inhibitor of the HCV nucleoside analogue and has shown its potent antiviral pangenotypic activity. The drug is effective when combined with other DAAs and when combined with ribavirin in genotype 2. Unlike PIs and NS5A inhibitors and within genotype 1, the drug is more effective against 1a. Its dosage is 400mg once a day, in 8 to 24-week regimens.<a class="elsevierStyleCrossRef" href="#bib0315">27</a> Sofosbuvir is a safe drug, with few interaction problems, but is not recommended for patients with an estimated glomerular filtration rate <30mL/min/1.73m2. One of the drug's most distinctive features is its high genetic barrier, with no reports of selection of resistant mutations after failures.<a class="elsevierStyleCrossRef" href="#bib0315">27</a> This feature makes the drug essential for rescue treatments.RibavirinAlthough not a DAA, ribavirin is still used for treating HCV, when combined with other drugs.<a class="elsevierStyleCrossRef" href="#bib0235">11</a> The drug is used at dosages of 800 to 1200mg a day, adjusted for weight and renal function, in 2 separate doses. Its current use is limited as a supplementary drug in DAA combinations that have shown increased efficacy. Ribavirin's main adverse effect is hemolytic anemia.Coformulated drugsParitaprevir/ritonavir/ombitasvir (Viekirax®, Abbvie) with or without dasabuvir (Exviera®, Abbvie)These drugs are known as the Abbvie 2D and 3D combos. The first drug combines a ritonavir-boosted HCV PI (paritaprevir) and an NS5A inhibitor (ombitasvir) in a single pill. The dosage is 2 tablets once a day. The drug is indicated for the treatment of patients with genotypes 1 and 4. For patients with genotype 1, the drug is combined with dasabuvir; if the genotype is 1a, ribavirin is also added. Dasabuvir is not used for patients with genotype 4 but is combined with ribavirin.<a class="elsevierStyleCrossRef" href="#bib0320">28</a>Reviewing all potential interactions is recommended before starting treatment. If the patient is HIV positive, it is important that the HIV viral load be undetectable with its antiretroviral therapy before starting this regimen that includes ritonavir, to prevent the development of resistances.<a class="elsevierStyleCrossRef" href="#bib0320">28</a> An adjustment is not necessary in the event of renal failure. The drug should not be used in patients with advanced liver disease (Child–Pugh classes B and C)<a class="elsevierStyleCrossRef" href="#bib0320">28</a> or in patients who have previously failed regimens with other PIs.<a class="elsevierStyleCrossRef" href="#bib0320">28</a>Dasabuvir is a non-nucleoside analogue polymerase inhibitor of HCV and is only active against genotype 1. The drug has less potency than other DAAs and is therefore always used in combination with paritaprevir/ritonavir and ombitasvir. Dasabuvir is well tolerated and safe and is administered every 12h.The combination of paritaprevir/ritonavir, ombitasvir and dasabuvir for treating HCV is considered a safe and well-tolerated regimen, with a high success rate (greater than 90%) and a lower cost than other therapeutic options. The combination has also been shown safe in renal failure and does not require dose adjustment. However, its disadvantages are the larger number of pills than other therapeutic options, the need for twice daily administration and the larger number of drug interactions.<a class="elsevierStyleCrossRef" href="#bib0260">16</a>Grazoprevir/elbasvir (Zepatier®, MSD)This recently approved formulation combines 100mg of grazoprevir (HCV PI) and 50mg of elbasvir (NS5A inhibitor) in a single tablet, administered once a day.<a class="elsevierStyleCrossRef" href="#bib0325">29</a> The combination is approved for genotypes 1, 4 and 6 and has shown its efficacy in patients coinfected with HIV and in advanced kidney disease stages IV and V, including patients undergoing dialysis. Its efficacy is above 90%. However, the response rates are lower in genotype 1 when there are baseline NS5A resistance-associated polymorphisms at positions 28, 30, 31 or 93.<a class="elsevierStyleCrossRef" href="#bib0325">29</a> In these cases or when a baseline resistance test is unavailable, it is advisable to add ribavirin and extend the treatment to 16 weeks.<a class="elsevierStyleCrossRef" href="#bib0325">29</a> If a patient has previously been treated with an HCV PI, it is advisable to add ribavirin.Sofosbuvir/ledipasvir (Harvoni®, Gilead)This combination includes 400mg of sofosbuvir and 90mg of ledipasvir (an NS5A inhibitor) in a single tablet. This was the first drug combination marketed for the treatment of HCV. There is extensive experience with patients with genotypes 1 and 4, in any stage of fibrosis, including decompensated cirrhosis.<a class="elsevierStyleCrossRef" href="#bib0330">30</a> The success rate of this combination in genotypes 1 and 4 is above 90%. The combination is less effective for genotype 3, with which there is less experience.For patients with genotype 1a for whom other regimens have failed, it has been shown that the presence of mutations that confer high resistance to ledipasvir significantly decreases the treatment efficacy. Therefore, if these mutations are present or cannot be ruled out, adding ribavirin to treatment regimen is recommended.This combination has few drug interactions.<a class="elsevierStyleCrossRef" href="#bib0260">16</a> Ledipasvir requires a low gastric pH for its absorption, and proton pump inhibitors can decrease its efficacy. When administered with tenofovir and an HIV PI, the patient's renal function should be monitored.<a class="elsevierStyleCrossRef" href="#bib0335">31</a> As with the use of sofosbuvir in isolation, there is barely any experience when the glomerular filtration rate is lower than 30mL/min/1.73m2.Sofosbuvir/velpatasvir (Epclusa®, Gilead)This new combination of sofosbuvir and a second-generation NS5A inhibitor improves the activity against genotypes 2 and 3, compared with ledipasvir.<a class="elsevierStyleCrossRef" href="#bib0340">32</a> This combination is pangenotypic and is approved for genotypes 1 to 6. The treatment duration is generally 12 weeks, except for decompensated cirrhosis with genotype 3. It is advisable to combine ribavirin only for decompensated cirrhosis and for pretreated patients or those with cirrhosis with the Y93H mutation and genotype 3 (because the presence of this mutation in these patients is associated with reduced response). The combinations main adverse effects are headache, fatigue, irritability and nausea. The effects are usually mild and do not usually require withdrawal of the drug.Indications for treatmentIt is recommended that all patients with active HCV infection start treatment,<a class="elsevierStyleCrossRef" href="#bib0230">10</a> whose objective is to reduce morbidity and mortality. In decompensated cirrhosis, the possibility of DAA treatment has changed these patients’ natural history, although the indication for transplantation cannot always be avoided.<a class="elsevierStyleCrossRef" href="#bib0345">33</a>Treatment in less advanced stages of fibrosis has been associated with a higher success rate, a possibility of healing with shorter treatments and fewer adverse effects. The effect of treatment on reducing transmission and eradicating the HCV infection is increasingly significant.<a class="elsevierStyleCrossRef" href="#bib0350">34</a>Practical aspects of the treatment of chronic liver disease due to HCVBefore starting HCV treatment, we need the results of general laboratory tests, the HCV genotype and subtype, the viral load and the degree of hepatic fibrosis (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). We need to know the history of previous antiviral treatment failures and assess the presence of comorbidities. It is important to determine the concomitant medication and review the potential interactions with the DAAs. A simple, fast and reliable way to do this is to use the University of Liverpool website (hep-druginteractions.org).<a class="elsevierStyleCrossRef" href="#bib0260">16</a> It is also essential that patients be aware of the importance of good treatment adherence.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Except in highly specific circumstances that have already been mentioned, the baseline resistances of the virus prior to the start of treatment have no impact on the SVR.<a class="elsevierStyleCrossRef" href="#bib0355">35</a> Performing a baseline resistances study to guide the treatment regimen is therefore not recommended.For patients with advanced fibrosis (F3-F4), an abdominal ultrasound should be available to rule out hepatocarcinoma. Patients with cirrhosis and transient elastography readings higher than 20kPa should also undergo upper endoscopy for the screening of esophageal varices.<a class="elsevierStyleCrossRef" href="#bib0360">36</a> As with patients with advanced fibrosis and cirrhosis, the SVR does not fully discount the possibility of developing an hepatocarcinoma. Abdominal ultrasonography should be continued, performing it every 6 months, regardless of whether the HCV is cured. During follow-up, the only essential viral load is that measured 12 weeks after ending the treatment; this reading will determine the SVR.<a class="elsevierStyleCrossRef" href="#bib0235">11</a>Treatment regimensHCV treatment currently consists of the combination of at least 2 DAAs with different targets against the virus.<a class="elsevierStyleCrossRef" href="#bib0235">11</a> Ribavirin is added in those situations in which it has been shown to increase the possibility of achieving an SVR. Treatment duration varies from 8 to 24 weeks; longer regimens are indicated for patients with decompensated cirrhosis. The main characteristics of the employed combinations are summarized in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>. The treatment guidelines from the following associations should be reviewed in all cases: the Spanish Association for the Study of the Liver, the Spanish Society of Infectious Diseases and Clinical Microbiology,<a class="elsevierStyleCrossRef" href="#bib0235">11</a> the European Association for the Study of the Liver<a class="elsevierStyleCrossRef" href="#bib0230">10</a> and the American Association for the Study of Liver Diseases.<a class="elsevierStyleCrossRef" href="#bib0225">9</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>The financial cost should also be considered when selecting the treatment regimen. In Spain, the price of the various drugs varies among the autonomous communities. It is therefore important to consult the local guidelines that assess the cost-effectiveness of the drugs.The recommended treatment regimens according to HCV genotype are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Combinations with simeprevir or daclatasvir are not included (the latter except for genotypes 2 and 3), because they offer no advantages over other more comfortable combinations with greater experience and lower cost. In the European guidelines, simeprevir appears as an alternative in genotype 4, both in cirrhosis and in no cirrhosis. Daclatasvir appears as an alternative for 12 or 24 weeks, with or without ribavirin, in all genotypes.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Conflict of interestsC. Quereda has participated in consulting activities for AbbVie, Gilead and MSD laboratories, as a speaker in AbbVie meetings and has occasionally attended congresses with funding from AbbVie, Gilead and Jansen." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres964031" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec934100" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres964032" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec934101" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Replication cycle of the hepatitis C virus. Therapeutic targets" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Direct-acting antivirals. Classification according to their mechanism of action" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "NS3/4A protease inhibitors" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "NS5A inhibitors" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "NS5B polymerase inhibitors" ] ] ] 7 => array:3 [ "identificador" => "sec0035" "titulo" => "Characteristics of the available drugs for HCV treatment" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0040" "titulo" => "Drugs without coformulation" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Simeprevir (Olysio, Janssen)" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Daclatasvir (Daklinza, BMS)" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Sofosbuvir (Sovaldi, Gilead)" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Ribavirin" ] ] ] 1 => array:3 [ "identificador" => "sec0065" "titulo" => "Coformulated drugs" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Paritaprevir/ritonavir/ombitasvir (Viekirax, Abbvie) with or without dasabuvir (Exviera, Abbvie)" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Grazoprevir/elbasvir (Zepatier, MSD)" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Sofosbuvir/ledipasvir (Harvoni, Gilead)" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Sofosbuvir/velpatasvir (Epclusa, Gilead)" ] ] ] ] ] 8 => array:2 [ "identificador" => "sec0090" "titulo" => "Indications for treatment" ] 9 => array:2 [ "identificador" => "sec0095" "titulo" => "Practical aspects of the treatment of chronic liver disease due to HCV" ] 10 => array:2 [ "identificador" => "sec0100" "titulo" => "Treatment regimens" ] 11 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interests" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-01-30" "fechaAceptado" => "2017-07-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec934100" "palabras" => array:2 [ 0 => "Hepatitis C virus" 1 => "Direct-acting antivirals" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec934101" "palabras" => array:2 [ 0 => "Virus de la hepatitis C" 1 => "Antivirales de acción directa" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Hepatitis C virus infection is a significant public health problem. The introduction of direct-acting antiviral agents, whose efficacy is greater than 90% in all patient groups (including those with cirrhosis), has represented a highly relevant change compared with classical interferon-based therapies. Tolerance for these antiviral agents is significantly better, and the treatment duration is shorter. This review updates the treatment of hepatitis C virus infection with the new direct-acting antiviral agents." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La infección por el virus de la hepatitis C constituye un problema importante de salud pública. La introducción de los antivirales de acción directa, cuya eficacia es superior al 90% en todos los grupos de pacientes, incluidos los cirróticos, ha supuesto un cambio muy relevante respecto al tratamiento con las terapias clásicas basadas en interferón. Además, la tolerancia de estos antivirales es significativamente mejor, y la duración del tratamiento más corta. Esta revisión pretende actualizar el tratamiento de la infección por el virus hepatitis C con los nuevos antivirales de acción directa." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Vivancos MJ, Moreno A, Quereda C. Tratamiento del virus de la hepatitis C con antivirales de acción directa: Aspectos prácticos y situación actual. Rev Clin Esp. 2018;218:29–37." ] ] "multimedia" => array:4 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1528 "Ancho" => 2353 "Tamanyo" => 232489 ] ] "descripcion" => array:1 [ "en" => "Replication cycle of hepatitis C virus and therapeutic targets." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2058 "Ancho" => 2489 "Tamanyo" => 245623 ] ] "descripcion" => array:1 [ "en" => "Factors to consider when selecting the therapeutic regimen." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2618 "Ancho" => 2910 "Tamanyo" => 652451 ] ] "descripcion" => array:1 [ "en" => "Characteristics of the various drug families for the hepatitis C virus." ] ] 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:3 [ "leyenda" => "Abbreviations: DAA, direct-acting antivirals; DCV, daclatasvir; DSV, dasabuvir; EBR, elbasvir; GZR, grazoprevir; HCV, hepatitis C virus; LDV, ledipasvir; OBV, ombitasvir; PI, protease inhibitor; PTV, paritaprevir; RBV, ribavirin; RTV, ritonavir; SOF, sofosbuvir; VEL, velpatasvir; VL, baseline viral load of HCV; w, weeks of treatment." "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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genotype \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Regimens \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Duration and special considerations \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">1a</td><td class="td" title="table-entry " align="left" valign="top">SOF+LDV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Only 8w: for treatment-naive, CV≤6×106UI/mL, and no cirrhosis (caution in F3) 12w without RBV: naive with or without compensated cirrhosis; pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> without compensated cirrhosis if there are no resistances in NS5A 12w+RBV: for decompensated cirrhosis For pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> with NS5A resistances or without being able to rule them out, with or without cirrhosis 24w: for the previous case and contraindication for RBV 24w+RBV: for patients with liver transplants and decompensated cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PTV/RTV+OBV+DSV+RBV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w: for no cirrhosis; 24w: for compensated cirrhosis Should not be used for decompensated cirrhosis or for previous failures with PI \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GZR+EBR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w without RBV: if there are no resistances to EBV or if CV ≤800,000IU/mL 16w+RBV: if there is resistance to EBV (or test is not available) and/or CV >800,000IU/mL Should not be used for decompensated cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF+VEL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w 12w+RBV: for decompensated cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">1b</td><td class="td" title="table-entry " align="left" valign="top">SOF+LDV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Only 8w: for treatment-naive, CV≤6×106UI/mL, and no cirrhosis (caution in F3) 12w without RBV: naive with CV>6×106IU/mL or cirrhosis; pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> without cirrhosis 12w+RBV: in pretreated<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> compensated cirrhosis<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a>; in decompensated cirrhosis 24w+RBV: for patients with liver transplants and decompensated cirrhosis 24w without RBV: if there is an indication for RBV and with contraindication for the same \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PTV/RTV+OBV+DSV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w without RBV 8w without RBV: for treatment-naive and no cirrhosis (caution in F3) Should not be used for decompensated cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GZR+EBR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w Should not be used for decompensated cirrhosis Add RBV if previous failure to PI \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF+VEL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">2</td><td class="td" title="table-entry " align="left" valign="top">SOF+RBV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w; 24 s: for cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF+DCV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w: scarce experience with this regimen; add RBV: for decompensated cirrhosis 16–24w: for compensated cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF+VEL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w; add RBV: for decompensated cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">3</td><td class="td" title="table-entry " align="left" valign="top">SOF+DCV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w: treatment-naive without cirrhosis; for pretreated<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> only if no Y93H mutation 12w with RBV: for pretreated without cirrhosis and with the Y93H resistance mutation or with no available resistance test 24w with RBV: for compensated or decompensated cirrhosis 24w: if RBV is recommended and contraindication to receive it \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF+VEL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w: for treatment-naive without cirrhosis; for pretreated<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> or cirrhosis, only if there is no Y93H mutation 12w with RBV: for pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> or those with cirrhosis and with the Y93H resistance mutation or with no available resistance test 24w with RBV: for compensated cirrhosis 24w: if RBV is recommended and contraindication to receive it \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">4</td><td class="td" title="table-entry " align="left" valign="top">SOF+LDV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w: treatment-naive 12w+RBV: for pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> and for decompensated cirrhosis 24w: if RBV is recommended and contraindication to receive it \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PTV/RTV+OBV+RBV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12s +/− RBV (if there are problems with RBV, the regimen without RBV can be administered) Should not be used for decompensated cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GZR+EBR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w 16s with RBV: assess this regimen in pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> and CV <800,000IU/mL Should not be used for decompensated cirrhosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF+VEL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12w 12w with RBV: for decompensated cirrhosis 24s: in decompensated cirrhosis and contraindication for RBV \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1633349.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Pretreated refers to a previous failure with regimens with interferon and RBV+/− first-generation PI. For failures with DAA, consult an expert." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "The European guidelines recommend 12 weeks without RBV, while the American guidelines recommend 12 weeks with RBV." ] ] ] "descripcion" => array:1 [ "en" => "Treatment regimens for chronic hepatitis C virus infection according to genotype." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:36 [ 0 => array:3 [ "identificador" => "bib0185" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "K. Mohd Hanafiah" 1 => "J. Groeger" 2 => "A.D. Flaxman" 3 => "S.T. 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Treatment of hepatitis C virus with direct-acting antivirals: Practical aspects and current situation

Tratamiento del virus de la hepatitis C con antivirales de acción directa: Aspectos prácticos y situación actual

M.J. Vivancos, A. Moreno, C. Quereda

Corresponding author

carmen.quereda@salud.madrid.org

Corresponding author.

Servicio de Enfermedades Infecciosas, Hospital Ramón y Cajal, Madrid, Spain

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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Replication cycle of hepatitis C virus and therapeutic targets&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">The hepatitis C virus &#40;HCV&#41; affects more than 170 million individuals worldwide&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">1&#44;2</span></a> HCV is the main cause of hepatic cirrhosis and hepatocarcinoma and is the most common indication for liver transplantation&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">3&#44;4</span></a> Half a million individuals die every year from HCV-related liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The HCV genome does not integrate with that of the host&#44; and therefore its replication can be definitively inhibited&#44; curing the infection&#46; It has been shown that the sustained viral response &#40;SVR&#41; achieved with HCV treatment improves the histology and progression of liver disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">6&#44;7</span></a> Chronic liver disease due to HCV began to be treated in 1991 with subcutaneous interferon alpha in monotherapy&#46; The efficacy of this treatment regimen was low&#44; and tolerance was poor&#46; In 1998&#44; ribavirin was included in the treatment&#44; improving the SVR rates but without significantly increasing the adverse effects of interferon&#46; In 2000&#44; conventional interferon alpha was replaced by pegylated interferon &#40;alpha 2a or alpha 2b&#41;&#44; improving the response and tolerance&#46; Neither interferon nor ribavirin have a direct antiviral effect against HCV but instead act by an immune-mediated mechanism&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Telaprevir and boceprevir&#44; the first direct-acting antivirals &#40;DAAs&#41; employed for treating chronic HCV infection&#44; were marketed in 2011&#46; Their mechanism of action inhibits the HCV protease &#40;PI&#41;&#46; These DAAs were approved for treatment in combination with pegylated interferon and ribavirin&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">8</span></a> Although this treatment regimen achieved a significant increase in the percentage of patients with SVR&#44; the regimen had significant limitations&#58; it was only effective for patients with genotype 1&#44; the treatment regimens were complex&#44; the number of pills were high&#44; the patients had intolerance or were contraindicated for interferon&#44; and the efficacy in subgroups with predictors of poor response continued to be low&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In 2013&#44; new DAAs began to appear&#44; which inhibited some of the steps in the virus replication cycle&#46; Using combinations of these drugs&#44; highly effective&#44; short and well-tolerated interferon-free treatment regimens have been achieved&#44; which have revolutionized HCV treatment&#44; even for patients with advanced stages of cirrhosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">9&#8211;11</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Replication cycle of the hepatitis C virus&#46; Therapeutic targets</span><p id="par0025" class="elsevierStylePara elsevierViewall">HCV is an RNA virus of the <span class="elsevierStyleItalic">Flaviviridae</span> family&#46; To date&#44; 6 genotypes have been described &#40;1a&#47;1b&#44; 2&#44; 3&#44; 4&#44; 5 and 6&#41;&#46; In Europe and the United States&#44; the most common genotype is 1&#44; followed by genotypes 3 and 4&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">1&#44;2</span></a> As with the human immunodeficiency virus &#40;HIV&#41;&#44; HCV has a high viral replication rate and a low error correction capability due to its polymerase RNA&#46; For patients with chronic infection&#44; these characteristics promote a considerable diversity of viral quasispecies&#46; However&#44; HCV does not integrate with the infected host&#39;s genome&#44; and HCV&#39;s entire cycle is performed in the cytoplasm&#46; Treatments that effectively block its replication can therefore eradicate the infection&#46; The replication cycle of HCV offers numerous therapeutic targets &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">The HCV virion enters the cells by endocytosis through a receptor&#46; HCV then releases its genome&#44; which is directed to the cell&#39;s endoplasmic reticulum&#44; where it forms a polyprotein of approximately 3011 amino acids through a translation process&#46; The HCV protease&#44; encoded by the NS3&#47;4A genome region&#44; is responsible &#40;along with other cell proteases&#41; for completing the hydrolysis of this polyprotein&#44; which is segmented into 3 structural and 7 nonstructural proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a> Inhibitors of this viral protease have been designed that bind to the viral&#39;s active center&#44; blocking its action and viral replication&#46; The composed proteins and the viral RNA interact with the NS5A protein&#44; which is associated with the membrane and is phosphorylated by a cell serine-kinase&#46; The NS5A protein has no known enzymatic function but is essential for RNA replication and the assembly of new viral particles&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a> NS5A inhibitors block the binding with proteins and inhibit the relationship between the NS5A protein and the locations of HCV intracellular replication&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Moreover&#44; a nonstructural RNA-dependent RNA polymerase protein &#40;NS5B&#41; is also involved in viral RNA replication&#44; which produces a negative-strand RNA and serves as a mold for manufacturing positive-strand RNA&#46; The NS5B nucleoside analogues incorporate in the RNA and block the chain&#44; inhibiting HCV replication through the binding to the enzyme&#39;s catalytic site &#40;conserved&#41;&#46; This area is common in all genotypes&#59; the drugs that act on this target are therefore active against all genotypes &#40;pangenotypics&#41;&#46; In contrast&#44; non-nucleoside NS5B inhibitors are noncompetitive inhibitors&#44; which block RNA synthesis before the start of the chain and are more dependent on the viral genotype&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a> The newly manufactured viral genomes can once again be replicated and translated or packaged to form new viral particles&#46; These new viral particles are released by exocytosis&#44; completing the cycle&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Direct-acting antivirals&#46; Classification according to their mechanism of action</span><p id="par0040" class="elsevierStylePara elsevierViewall">The currently available DAAs are classified according to the target of the HCV replication cycle on which they act&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">Protease inhibitors &#40;PI&#41; NS3&#47;4A&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">NS5A protein inhibitors&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">NS5B polymerase inhibitors&#44; which in turn can be nucleoside analogues and non-nucleoside analogues&#46;</p></li></ul></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">NS3&#47;4A protease inhibitors</span><p id="par0060" class="elsevierStylePara elsevierViewall">These agents act by inhibiting the HCV protease NS3&#47;4A and thereby the replication of the virus&#46; The drugs belonging to this family are named with the suffix &#8220;previr&#8221;&#46; Telaprevir and boceprevir were the first to be used and are therefore considered first-generation HCV PIs&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">14&#44;15</span></a> Due to their above-mentioned limitations&#44; the drugs were replaced by other PIs&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The second and third-generation PIs&#44; which have been marketed&#44; are polygenotypic drugs with activity against the HCV genotypes 1&#44; 2 and 4 &#40;although the drugs are not used for HCV genotype 2&#41;&#46; However&#44; the drugs have no activity against genotype 3&#44; and there is little experience with genotypes 5 to 7&#46; Within genotype 1&#44; the drugs are more active against subtype 1b&#46; The first-generation PIs have greater potency&#44; safety&#44; tolerance and a longer half-life&#44; which allow them to be administered once a day with fewer drug interactions&#46; Nevertheless&#44; potential interactions should be checked&#44; and the patient should be instructed not to take any new drug without a previous consultation&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">16</span></a> Although resistant mutations can be generated in patients treated with these drugs&#44; the genetic barrier of these drugs to resistance is much greater than that of first-generation PIs&#46; The resistance mutations generated during treatment with some of these drugs does not jeopardize the response with other drugs of the same family&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The currently approved HCV PIs in Europe and the US are simeprevir&#44; paritaprevir &#40;which are administered boosted with ritonavir&#41; and grazoprevir&#46; Glecaprevir &#40;AbbVie&#41;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">17</span></a> and voxilaprevir &#40;Gilead&#41;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">18</span></a> are 2 potent new-generation pangenotypic PIs&#44; with activity against genotype 3 and are currently in advanced phases of research&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">NS5A inhibitors</span><p id="par0075" class="elsevierStylePara elsevierViewall">These drugs act by inhibiting the NS5A replication complex&#46; The drugs that belong to this family are pangenotypic and are named with the suffix &#8220;asvir&#8221;&#46; As with the PIs&#44; the drugs have greater activity within genotype 1 against subtype 1b&#46; The drugs are potent&#44; well-tolerated and have pharmacokinetics that allows for administration once a day&#46; Their adverse effects are generally mild&#46; Although these drugs generally have fewer interactions than PIs&#44; the interactions should always be considered when these drugs are used concomitantly with other drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">16</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The currently approved NS5A inhibitors in Europe and the US are daclatasvir&#44; ombitasvir&#44; ledipasvir&#44; velpatasvir and elbasvir&#46; All but the first are coformulated with another DAA&#46; Pibrentasvir is a new NS5A inhibitor&#44; which will be used coformulated with glecaprevir &#40;AbbVie&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">17</span></a> The drug is still being researched&#44; but the results from phase III studies have been presented&#44; with excellent results in all genotypes&#44; without needing to add ribavirin&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">17</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The genetic barrier of this family of drugs is moderate&#46; Resistance mutations are frequently selected in patients who fail a treatment regimen that includes one of these drugs&#46; This possibility is lower with more modern NS5A inhibitors &#40;velpatasvir&#44; elbasvir and pibrentasvir&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">NS5B polymerase inhibitors</span><p id="par0090" class="elsevierStylePara elsevierViewall">These drugs act by inhibiting the HCV RNA polymerase NS5B&#46; Drugs belonging to this family are named with the suffix &#8220;buvir&#8221;&#46; There are 2 types of these drugs&#58; nucleoside analogues and non-nucleoside analogues&#46; We currently only have sofosbuvir in the first group and dasabuvir in the second&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The general characteristics of NS5B nucleoside analogue polymerase inhibitors are as follows&#58; &#40;1&#41; high antiviral potency&#59; &#40;2&#41; high barrier to resistance&#59; &#40;3&#41; pangenotypics&#59; &#40;4&#41; easy posology&#44; and &#40;5&#41; few adverse effects and interactions&#46; These characteristics make the drugs attractive as components of any treatment regimen&#46; In contrast&#44; NS5B non-nucleoside analogue polymerase inhibitors&#44; although safe and well-tolerated&#44; have low antiviral potency&#44; limited activity against genotype 1 and a low genetic barrier&#44; which frequently results in the appearance of strains with resistance mutations in the therapeutic failures&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Characteristics of the available drugs for HCV treatment</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Drugs without coformulation</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Simeprevir &#40;Olysio<span class="elsevierStyleSup">&#174;</span>&#44; Janssen&#41;</span><p id="par0100" class="elsevierStylePara elsevierViewall">This is a second-generation HCV PI that is effective in patients with genotypes 1 and 4&#46; Dosages of 150<span class="elsevierStyleHsp" style=""></span>mg a day are employed&#44; in 12 to 24-week regimens&#46; There is experience with the use of simeprevir combined with pegylated interferon and ribavirin&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">20</span></a> with sofosbuvir<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">21</span></a> and with daclatasvir&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">22</span></a> When combined with sofosbuvir&#44; simeprevir has shown SVR rates of more than 80&#37;&#59; the combination with ribavirin does not improve the results&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">23</span></a> When combined with daclatasvir&#44; the results are unsatisfactory&#44; and there is very little experience with this combination&#46; The response rates with simeprevir are lower in patients with genotype 1 and the Q80K mutation&#44; especially in regimens in which it is combined with interferon and ribavirin&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">20</span></a> The drug is not recommended for patients who have previously failed regimens with an HCV PI&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">24</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Simeprevir is a very well-tolerated drug&#44; with generally mild adverse effects&#46; The most common adverse effects include skin rashes&#44; photosensitivity and increased transaminase and bilirubin levels&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">25</span></a> The drug is not recommended for patients with advanced liver disease &#40;Child&#8211;Pugh classes B and C&#41;&#44; because the disease can increase its serum levels and its toxicity&#46; Interactions can occur with other cytochrome P450 3A inducers and inhibitors&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Due to its lower potency&#44; potential drug interactions and lack of coformulation with other agents against HCV&#44; simeprevir is rarely used and has been displaced by other options&#46; The drug can still have a certain usefulness for the few patients for whom other regimens with DAA fail&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Daclatasvir &#40;Daklinza<span class="elsevierStyleSup">&#174;</span>&#44; BMS&#41;</span><p id="par0115" class="elsevierStylePara elsevierViewall">This drug is a first-generation NS5A protein inhibitor&#44; active against genotypes 1 to 6&#46; Dosages of 60<span class="elsevierStyleHsp" style=""></span>mg a day are employed&#44; in 12 to 24-week regimens&#46; The dose must be reduced to 30<span class="elsevierStyleHsp" style=""></span>mg when used with atazanavir-ritonavir&#44; azole or clarithromycin&#46; If used along with efavirenz&#44; etravirine or dexamethasone&#44; the dosage should be increased to 90<span class="elsevierStyleHsp" style=""></span>mg a day&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">26</span></a> Although there is experience with the drug combined with various DAAs&#44; the most studied and effective regimen is the combination with sofosbuvir&#44; with or without ribavirin&#46; Despite its safety and efficacy&#44; the regimen is not a first-choice regimen&#44; because there are other more comfortable options with better cost-efficiency&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Sofosbuvir &#40;Sovaldi<span class="elsevierStyleSup">&#174;</span>&#44; Gilead&#41;</span><p id="par0120" class="elsevierStylePara elsevierViewall">This is an NS5B polymerase inhibitor of the HCV nucleoside analogue and has shown its potent antiviral pangenotypic activity&#46; The drug is effective when combined with other DAAs and when combined with ribavirin in genotype 2&#46; Unlike PIs and NS5A inhibitors and within genotype 1&#44; the drug is more effective against 1a&#46; Its dosage is 400<span class="elsevierStyleHsp" style=""></span>mg once a day&#44; in 8 to 24-week regimens&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">27</span></a> Sofosbuvir is a safe drug&#44; with few interaction problems&#44; but is not recommended for patients with an estimated glomerular filtration rate &#60;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; One of the drug&#39;s most distinctive features is its high genetic barrier&#44; with no reports of selection of resistant mutations after failures&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">27</span></a> This feature makes the drug essential for rescue treatments&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Ribavirin</span><p id="par0125" class="elsevierStylePara elsevierViewall">Although not a DAA&#44; ribavirin is still used for treating HCV&#44; when combined with other drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">11</span></a> The drug is used at dosages of 800 to 1200<span class="elsevierStyleHsp" style=""></span>mg a day&#44; adjusted for weight and renal function&#44; in 2 separate doses&#46; Its current use is limited as a supplementary drug in DAA combinations that have shown increased efficacy&#46; Ribavirin&#39;s main adverse effect is hemolytic anemia&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Coformulated drugs</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Paritaprevir&#47;ritonavir&#47;ombitasvir &#40;Viekirax<span class="elsevierStyleSup">&#174;</span>&#44; Abbvie&#41; with or without dasabuvir &#40;Exviera<span class="elsevierStyleSup">&#174;</span>&#44; Abbvie&#41;</span><p id="par0130" class="elsevierStylePara elsevierViewall">These drugs are known as the Abbvie 2D and 3D combos&#46; The first drug combines a ritonavir-boosted HCV PI &#40;paritaprevir&#41; and an NS5A inhibitor &#40;ombitasvir&#41; in a single pill&#46; The dosage is 2 tablets once a day&#46; The drug is indicated for the treatment of patients with genotypes 1 and 4&#46; For patients with genotype 1&#44; the drug is combined with dasabuvir&#59; if the genotype is 1a&#44; ribavirin is also added&#46; Dasabuvir is not used for patients with genotype 4 but is combined with ribavirin&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">28</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Reviewing all potential interactions is recommended before starting treatment&#46; If the patient is HIV positive&#44; it is important that the HIV viral load be undetectable with its antiretroviral therapy before starting this regimen that includes ritonavir&#44; to prevent the development of resistances&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">28</span></a> An adjustment is not necessary in the event of renal failure&#46; The drug should not be used in patients with advanced liver disease &#40;Child&#8211;Pugh classes B and C&#41;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">28</span></a> or in patients who have previously failed regimens with other PIs&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">28</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Dasabuvir is a non-nucleoside analogue polymerase inhibitor of HCV and is only active against genotype 1&#46; The drug has less potency than other DAAs and is therefore always used in combination with paritaprevir&#47;ritonavir and ombitasvir&#46; Dasabuvir is well tolerated and safe and is administered every 12<span class="elsevierStyleHsp" style=""></span>h&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The combination of paritaprevir&#47;ritonavir&#44; ombitasvir and dasabuvir for treating HCV is considered a safe and well-tolerated regimen&#44; with a high success rate &#40;greater than 90&#37;&#41; and a lower cost than other therapeutic options&#46; The combination has also been shown safe in renal failure and does not require dose adjustment&#46; However&#44; its disadvantages are the larger number of pills than other therapeutic options&#44; the need for twice daily administration and the larger number of drug interactions&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Grazoprevir&#47;elbasvir &#40;Zepatier<span class="elsevierStyleSup">&#174;</span>&#44; MSD&#41;</span><p id="par0150" class="elsevierStylePara elsevierViewall">This recently approved formulation combines 100<span class="elsevierStyleHsp" style=""></span>mg of grazoprevir &#40;HCV PI&#41; and 50<span class="elsevierStyleHsp" style=""></span>mg of elbasvir &#40;NS5A inhibitor&#41; in a single tablet&#44; administered once a day&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">29</span></a> The combination is approved for genotypes 1&#44; 4 and 6 and has shown its efficacy in patients coinfected with HIV and in advanced kidney disease stages IV and V&#44; including patients undergoing dialysis&#46; Its efficacy is above 90&#37;&#46; However&#44; the response rates are lower in genotype 1 when there are baseline NS5A resistance-associated polymorphisms at positions 28&#44; 30&#44; 31 or 93&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">29</span></a> In these cases or when a baseline resistance test is unavailable&#44; it is advisable to add ribavirin and extend the treatment to 16 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">29</span></a> If a patient has previously been treated with an HCV PI&#44; it is advisable to add ribavirin&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Sofosbuvir&#47;ledipasvir &#40;Harvoni<span class="elsevierStyleSup">&#174;</span>&#44; Gilead&#41;</span><p id="par0155" class="elsevierStylePara elsevierViewall">This combination includes 400<span class="elsevierStyleHsp" style=""></span>mg of sofosbuvir and 90<span class="elsevierStyleHsp" style=""></span>mg of ledipasvir &#40;an NS5A inhibitor&#41; in a single tablet&#46; This was the first drug combination marketed for the treatment of HCV&#46; There is extensive experience with patients with genotypes 1 and 4&#44; in any stage of fibrosis&#44; including decompensated cirrhosis&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">30</span></a> The success rate of this combination in genotypes 1 and 4 is above 90&#37;&#46; The combination is less effective for genotype 3&#44; with which there is less experience&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">For patients with genotype 1a for whom other regimens have failed&#44; it has been shown that the presence of mutations that confer high resistance to ledipasvir significantly decreases the treatment efficacy&#46; Therefore&#44; if these mutations are present or cannot be ruled out&#44; adding ribavirin to treatment regimen is recommended&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">This combination has few drug interactions&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">16</span></a> Ledipasvir requires a low gastric pH for its absorption&#44; and proton pump inhibitors can decrease its efficacy&#46; When administered with tenofovir and an HIV PI&#44; the patient&#39;s renal function should be monitored&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">31</span></a> As with the use of sofosbuvir in isolation&#44; there is barely any experience when the glomerular filtration rate is lower than 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;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Sofosbuvir&#47;velpatasvir &#40;Epclusa<span class="elsevierStyleSup">&#174;</span>&#44; Gilead&#41;</span><p id="par0170" class="elsevierStylePara elsevierViewall">This new combination of sofosbuvir and a second-generation NS5A inhibitor improves the activity against genotypes 2 and 3&#44; compared with ledipasvir&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">32</span></a> This combination is pangenotypic and is approved for genotypes 1 to 6&#46; The treatment duration is generally 12 weeks&#44; except for decompensated cirrhosis with genotype 3&#46; It is advisable to combine ribavirin only for decompensated cirrhosis and for pretreated patients or those with cirrhosis with the Y93H mutation and genotype 3 &#40;because the presence of this mutation in these patients is associated with reduced response&#41;&#46; The combinations main adverse effects are headache&#44; fatigue&#44; irritability and nausea&#46; The effects are usually mild and do not usually require withdrawal of the drug&#46;</p></span></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Indications for treatment</span><p id="par0175" class="elsevierStylePara elsevierViewall">It is recommended that all patients with active HCV infection start treatment&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">10</span></a> whose objective is to reduce morbidity and mortality&#46; In decompensated cirrhosis&#44; the possibility of DAA treatment has changed these patients&#8217; natural history&#44; although the indication for transplantation cannot always be avoided&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">33</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Treatment in less advanced stages of fibrosis has been associated with a higher success rate&#44; a possibility of healing with shorter treatments and fewer adverse effects&#46; The effect of treatment on reducing transmission and eradicating the HCV infection is increasingly significant&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Practical aspects of the treatment of chronic liver disease due to HCV</span><p id="par0185" class="elsevierStylePara elsevierViewall">Before starting HCV treatment&#44; we need the results of general laboratory tests&#44; the HCV genotype and subtype&#44; the viral load and the degree of hepatic fibrosis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; We need to know the history of previous antiviral treatment failures and assess the presence of comorbidities&#46; It is important to determine the concomitant medication and review the potential interactions with the DAAs&#46; A simple&#44; fast and reliable way to do this is to use the University of Liverpool website &#40;hep-druginteractions&#46;org&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">16</span></a> It is also essential that patients be aware of the importance of good treatment adherence&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">Except in highly specific circumstances that have already been mentioned&#44; the baseline resistances of the virus prior to the start of treatment have no impact on the SVR&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">35</span></a> Performing a baseline resistances study to guide the treatment regimen is therefore not recommended&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">For patients with advanced fibrosis &#40;F3-F4&#41;&#44; an abdominal ultrasound should be available to rule out hepatocarcinoma&#46; Patients with cirrhosis and transient elastography readings higher than 20<span class="elsevierStyleHsp" style=""></span>kPa should also undergo upper endoscopy for the screening of esophageal varices&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a> As with patients with advanced fibrosis and cirrhosis&#44; the SVR does not fully discount the possibility of developing an hepatocarcinoma&#46; Abdominal ultrasonography should be continued&#44; performing it every 6 months&#44; regardless of whether the HCV is cured&#46; During follow-up&#44; the only essential viral load is that measured 12 weeks after ending the treatment&#59; this reading will determine the SVR&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Treatment regimens</span><p id="par0200" class="elsevierStylePara elsevierViewall">HCV treatment currently consists of the combination of at least 2 DAAs with different targets against the virus&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">11</span></a> Ribavirin is added in those situations in which it has been shown to increase the possibility of achieving an SVR&#46; Treatment duration varies from 8 to 24 weeks&#59; longer regimens are indicated for patients with decompensated cirrhosis&#46; The main characteristics of the employed combinations are summarized in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46; The treatment guidelines from the following associations should be reviewed in all cases&#58; the Spanish Association for the Study of the Liver&#44; the Spanish Society of Infectious Diseases and Clinical Microbiology&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">11</span></a> the European Association for the Study of the Liver<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">10</span></a> and the American Association for the Study of Liver Diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">9</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0205" class="elsevierStylePara elsevierViewall">The financial cost should also be considered when selecting the treatment regimen&#46; In Spain&#44; the price of the various drugs varies among the autonomous communities&#46; It is therefore important to consult the local guidelines that assess the cost-effectiveness of the drugs&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The recommended treatment regimens according to HCV genotype are listed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Combinations with simeprevir or daclatasvir are not included &#40;the latter except for genotypes 2 and 3&#41;&#44; because they offer no advantages over other more comfortable combinations with greater experience and lower cost&#46; In the European guidelines&#44; simeprevir appears as an alternative in genotype 4&#44; both in cirrhosis and in no cirrhosis&#46; Daclatasvir appears as an alternative for 12 or 24 weeks&#44; with or without ribavirin&#44; in all genotypes&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interests</span><p id="par0215" class="elsevierStylePara elsevierViewall">C&#46; Quereda has participated in consulting activities for AbbVie&#44; Gilead and MSD laboratories&#44; as a speaker in AbbVie meetings and has occasionally attended congresses with funding from AbbVie&#44; Gilead and Jansen&#46;</p></span></span>"
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          "titulo" => "Replication cycle of the hepatitis C virus&#46; Therapeutic targets"
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          "titulo" => "Direct-acting antivirals&#46; Classification according to their mechanism of action"
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              "titulo" => "NS3&#47;4A protease inhibitors"
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          "titulo" => "Characteristics of the available drugs for HCV treatment"
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                  "titulo" => "Simeprevir &#40;Olysio&#44; Janssen&#41;"
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                  "titulo" => "Paritaprevir&#47;ritonavir&#47;ombitasvir &#40;Viekirax&#44; Abbvie&#41; with or without dasabuvir &#40;Exviera&#44; Abbvie&#41;"
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                  "titulo" => "Grazoprevir&#47;elbasvir &#40;Zepatier&#44; MSD&#41;"
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                  "titulo" => "Sofosbuvir&#47;ledipasvir &#40;Harvoni&#44; Gilead&#41;"
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                  "titulo" => "Sofosbuvir&#47;velpatasvir &#40;Epclusa&#44; Gilead&#41;"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hepatitis C virus infection is a significant public health problem&#46; The introduction of direct-acting antiviral agents&#44; whose efficacy is greater than 90&#37; in all patient groups &#40;including those with cirrhosis&#41;&#44; has represented a highly relevant change compared with classical interferon-based therapies&#46; Tolerance for these antiviral agents is significantly better&#44; and the treatment duration is shorter&#46; This review updates the treatment of hepatitis C virus infection with the new direct-acting antiviral agents&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La infecci&#243;n por el virus de la hepatitis C constituye un problema importante de salud p&#250;blica&#46; La introducci&#243;n de los antivirales de acci&#243;n directa&#44; cuya eficacia es superior al 90&#37; en todos los grupos de pacientes&#44; incluidos los cirr&#243;ticos&#44; ha supuesto un cambio muy relevante respecto al tratamiento con las terapias cl&#225;sicas basadas en interfer&#243;n&#46; Adem&#225;s&#44; la tolerancia de estos antivirales es significativamente mejor&#44; y la duraci&#243;n del tratamiento m&#225;s corta&#46; Esta revisi&#243;n pretende actualizar el tratamiento de la infecci&#243;n por el virus hepatitis C con los nuevos antivirales de acci&#243;n directa&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Vivancos MJ&#44; Moreno A&#44; Quereda C&#46; Tratamiento del virus de la hepatitis C con antivirales de acci&#243;n directa&#58; Aspectos pr&#225;cticos y situaci&#243;n actual&#46; Rev Clin Esp&#46; 2018&#59;218&#58;29&#8211;37&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; DAA&#44; direct-acting antivirals&#59; DCV&#44; daclatasvir&#59; DSV&#44; dasabuvir&#59; EBR&#44; elbasvir&#59; GZR&#44; grazoprevir&#59; HCV&#44; hepatitis C virus&#59; LDV&#44; ledipasvir&#59; OBV&#44; ombitasvir&#59; PI&#44; protease inhibitor&#59; PTV&#44; paritaprevir&#59; RBV&#44; ribavirin&#59; RTV&#44; ritonavir&#59; SOF&#44; sofosbuvir&#59; VEL&#44; velpatasvir&#59; VL&#44; baseline viral load of HCV&#59; w&#44; weeks of treatment&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Regimens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Duration and special considerations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">1a</td><td class="td" title="table-entry  " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LDV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Only 8<span class="elsevierStyleHsp" style=""></span>w&#58; for treatment-naive&#44; CV<span class="elsevierStyleHsp" style=""></span>&#8804;6<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>UI&#47;mL&#44; and no cirrhosis &#40;caution in F3&#41;<br>12<span class="elsevierStyleHsp" style=""></span>w without RBV&#58; naive with or without compensated cirrhosis&#59; pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> without compensated cirrhosis if there are no resistances in NS5A<br>12<span class="elsevierStyleHsp" style=""></span>w<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&#58; for decompensated cirrhosis<br>For pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> with NS5A resistances or without being able to rule them out&#44; with or without cirrhosis<br>24<span class="elsevierStyleHsp" style=""></span>w&#58; for the previous case and contraindication for RBV<br>24<span class="elsevierStyleHsp" style=""></span>w<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&#58; for patients with liver transplants and decompensated cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PTV&#47;RTV<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>OBV<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DSV<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w&#58; for no cirrhosis&#59; 24<span class="elsevierStyleHsp" style=""></span>w&#58; for compensated cirrhosis<br>Should not be used for decompensated cirrhosis or for previous failures with PI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GZR<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>EBR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w without RBV&#58; if there are no resistances to EBV or if CV &#8804;800&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;mL<br>16<span class="elsevierStyleHsp" style=""></span>w<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&#58; if there is resistance to EBV &#40;or test is not available&#41; and&#47;or CV &#62;800&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;mL<br>Should not be used for decompensated cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>VEL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w<br>12<span class="elsevierStyleHsp" style=""></span>w<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&#58; for decompensated cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">1b</td><td class="td" title="table-entry  " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LDV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Only 8<span class="elsevierStyleHsp" style=""></span>w&#58; for treatment-naive&#44; CV<span class="elsevierStyleHsp" style=""></span>&#8804;6<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>UI&#47;mL&#44; and no cirrhosis &#40;caution in F3&#41;<br>12<span class="elsevierStyleHsp" style=""></span>w without RBV&#58; naive with CV<span class="elsevierStyleHsp" style=""></span>&#62;6<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>IU&#47;mL or cirrhosis&#59; pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> without cirrhosis<br>12<span class="elsevierStyleHsp" style=""></span>w<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&#58; in pretreated<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> compensated cirrhosis<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&#59; in decompensated cirrhosis<br>24<span class="elsevierStyleHsp" style=""></span>w<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&#58; for patients with liver transplants and decompensated cirrhosis<br>24<span class="elsevierStyleHsp" style=""></span>w without RBV&#58; if there is an indication for RBV and with contraindication for the same&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PTV&#47;RTV<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>OBV<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DSV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w without RBV<br>8<span class="elsevierStyleHsp" style=""></span>w without RBV&#58; for treatment-naive and no cirrhosis &#40;caution in F3&#41;<br>Should not be used for decompensated cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GZR<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>EBR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w<br>Should not be used for decompensated cirrhosis<br>Add RBV if previous failure to PI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>VEL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">2</td><td class="td" title="table-entry  " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w&#59; 24 s&#58; for cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DCV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w&#58; scarce experience with this regimen&#59; add RBV&#58; for decompensated cirrhosis<br>16&#8211;24<span class="elsevierStyleHsp" style=""></span>w&#58; for compensated cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>VEL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w&#59; add RBV&#58; for decompensated cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">3</td><td class="td" title="table-entry  " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DCV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w&#58; treatment-naive without cirrhosis&#59; for pretreated<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> only if no Y93H mutation<br>12<span class="elsevierStyleHsp" style=""></span>w with RBV&#58; for pretreated without cirrhosis and with the Y93H resistance mutation or with no available resistance test<br>24<span class="elsevierStyleHsp" style=""></span>w with RBV&#58; for compensated or decompensated cirrhosis<br>24<span class="elsevierStyleHsp" style=""></span>w&#58; if RBV is recommended and contraindication to receive it&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>VEL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w&#58; for treatment-naive without cirrhosis&#59; for pretreated<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> or cirrhosis&#44; only if there is no Y93H mutation<br>12<span class="elsevierStyleHsp" style=""></span>w with RBV&#58; for pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> or those with cirrhosis and with the Y93H resistance mutation or with no available resistance test<br>24<span class="elsevierStyleHsp" style=""></span>w with RBV&#58; for compensated cirrhosis<br>24<span class="elsevierStyleHsp" style=""></span>w&#58; if RBV is recommended and contraindication to receive it&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">4</td><td class="td" title="table-entry  " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>LDV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w&#58; treatment-naive<br>12<span class="elsevierStyleHsp" style=""></span>w<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&#58; for pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> and for decompensated cirrhosis<br>24<span class="elsevierStyleHsp" style=""></span>w&#58; if RBV is recommended and contraindication to receive it&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PTV&#47;RTV<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>OBV<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RBV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>s &#43;&#47;&#8722; RBV &#40;if there are problems with RBV&#44; the regimen without RBV can be administered&#41;<br>Should not be used for decompensated cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">GZR<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>EBR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w<br>16<span class="elsevierStyleHsp" style=""></span>s with RBV&#58; assess this regimen in pretreated patients<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> and CV &#60;800&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;mL<br>Should not be used for decompensated cirrhosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">SOF<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>VEL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12<span class="elsevierStyleHsp" style=""></span>w<br>12<span class="elsevierStyleHsp" style=""></span>w with RBV&#58; for decompensated cirrhosis<br>24<span class="elsevierStyleHsp" style=""></span>s&#58; in decompensated cirrhosis and contraindication for RBV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab1633349.png"
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          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Pretreated refers to a previous failure with regimens with interferon and RBV&#43;&#47;&#8722; first-generation PI&#46; For failures with DAA&#44; consult an expert&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The European guidelines recommend 12 weeks without RBV&#44; while the American guidelines recommend 12 weeks with RBV&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Treatment regimens for chronic hepatitis C virus infection according to genotype&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2017.07.005

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