الفهرس 
Liver TransplantationOnly 14 pages are availabe for public view
 |  | from | 286 |  |  |
| | | from | 286 | | |
Abstract
C
hronic hepatitis C virus (HCV) infection genotype 4 occurs in approximately 13% of all HCV infections worldwide (Blach et al., 2016), with the highest prevalence occurring in Egypt, as 15 % of Egyptian population are infected with HCV and 93% are genotype 4 (Abdelsallam et al., 2017; Ahmed et al., 2017). Liver transplantation (LT) is considered a treatment in patients with end-stage liver disease, patients with the development of hepatocellular carcinoma (HCC) and those with acute liver failure whom LT provides the only chance of cure, long-term survival and improves quality of life (QoL) for them(Burra et al., 2016).
Post-transplant HCV recurrence is very common, and up to 90% of these patients subsequently develop chronic liver disease (Samonakis et al., 2012;Coilly et al., 2013), which progresses to cirrhosis within 5 years in 30% of patients (Gane, 2008) and is associated with a 44% increased risk of mortality (Martin et al., 2012).
The combination of pegylated interferon (pegIFN) and ribavirin (RBV) has been the only therapeutic option available for the last 20 years but it was rarely effective, particularly in patients with more advanced graft hepatitis (Belli et al., 2017).
Until recently, the therapeutic revolution in the management of chronic HCV infection was by the discovery of direct acting antiviral agents (DAAs) (Bertino et al., 2016). With the introduction of these approved DAAs, IFN-free combinations were broadly used (EASL, 2015).
The choice of calcineurin inhibitors (CNIs) has been proposed as a modifiable contributing factor to the occurrence of non-response to AVT among the LT population, partially because cyclosporine A (CsA) exerts its immunosuppressive effect through the protein target cyclophilin B (Samuel et al., 2007), which is an essential cofactor for HCV replication (Inoue et al., 2003). In vitro data have shown that CsA suppresses HCV RNA replication in replicon models and in human hepatocytes in a dose-dependent manner; this effect was not observed with tacrolimus (Tac) (Firpi et al., 2006;Berenguer et al., 2009; Cescon et al., 2009;Berenguer et al., 2010), which targets the FK506-binding protein. These in vitro data may reflect the clinical benefits of CsA therapy in HCV-positive LT patients (Hirano et al., 2008; Berenguer et al., 2009; Selzner et al., 2009).
Interferon (IFN) is not thought to act by inhibiting cyclophilin, which is supported by in vitro data showing that the inhibitory effect of CsA on HCV replication is independent of the IFN signalling pathways and contributes to its antiviral effect (Selzner et al., 2009).
A review of these reports supports a potential benefit of CsA in HCV-positive LT patients and indicates the need for additional studies to confirm this evidence (Shiffman et al., 2007a; Rabie et al., 2013). Therefore, it is possible that CsA-based immunosuppression may complement peg IFN-α 2a and RBV as antiviral therapy and enhance the SVR in LT patients with recurrent HCV infection.However, trials comparing the outcomes of peg IFN-α 2a and RBV as AVT with concomitant CsA versus Tac administration are relatively sparse and not done regarding DAA’s as AVT.
Therefore, this study was designed to explore whether LT patients treated with CsA versus Tac would have a higher SVR rate in response to different AVT regimens including peg IFN-α 2a plus RBV, sofosbuvir plus RBV, daclatasvir, sofosbuvir plus RBV with regard to HCV genotype 4 recurrence.
The study was a prospective cohort two- centre conducted on 126 LDLT recipients with recurrent HCVgenotype - 4. These patients were categorized into 3 groups according to the type of AVT received and each group was divided in to two sub groups according to the administered primary immunosuppression:
group I: Fourty four recipients received peg IFN-α 2a and RBV as AVT, tweenty recipients receiving cyclosporine A as primary immunosuppressive drug and twenty four recipients receiving tacrolimus as primary immunosuppressive drug.
group II: Fifty two recipients received sofosbuvir and RBV as AVT, tweenty one recipients receiving cyclosporine A as primary immunosuppressive drug and thirty one recipients receiving tacrolimus as primary immunosuppressive drug.
group III: Thirty received daclatasvir, sofosbuvir and RBV as AVT, tweleve recipients receiving cyclosporine A as primary immunosuppressive drug and eighteen recipients receiving tacrolimus as primary immunosuppressive drug.
The treatment period for group I, included 48 weeks of AVT and follow up of 24 weeks after AVT cessation. For groups II and III; the treatment period included 24 weeks of AVT and follow up of 12 weeks after AVT cessation.
The primary endpoint was the achievement of an SVR defined by a negative serum HCV RNA test at the end of 24 weeks for group I and at the end of 12 weeks for groups II and III after AVT cessation.
The secondary endpoints include relapse rate defined as reappearance of HCV RNA during the follow up period in patients who achieved an end of treatment (EOT) virological response and also the biochemical responses (ALT, AST, ALP and T.Bil) levels for all treatments groups. For group I additional secondary end points included an EVR (a negative HCV RNA test at week 12 after the start of AVT), a delayed virological response (DVR, a negative HCV RNA test at week 24 after the start of AVT) and an end of treatment (EOT) virological response (a negative HCV RNA test at week 48 after the start of AVT).Additional secondary endpoints for groups II and III included, a HCV RNA test at week 4 after the start of AVT and an EOT at week 24 after the start of AVT.
Also, the risk factors associated with HCV relapse after AVT cessation were investigated as a secondary end point including (patients age,gender and BMI- donor age and gender-pretreatment viral load-pre AVT use failure-co-morbidity as diabetes mellitus-CMV infection-type of immunosuppression-concomittant use of MMF –RBV dose reduction or interruption).