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Background Hepatitis C virus ( HCV) recurrence after liver transplantation ( LT) used to be a serious problem in the era of interferon-based treatment. Since the introduction of modern directly acting antivirals, treatment has become easier and shorter. According to published data, in the natural course of hepatitis C infection the duration of antiviral treatment with sofosbuvir ( SOF) and ledipasvir ( LDV) may be shortened to 12 instead of 24 weeks, using ribavirin ( RBV) in addition. Furthermore, the question of whether or not RBV is really necessary, in a 12-week SOF/ LDV treatment in the post-transplant setting, is still unanswered. Patients and methods At our institution, 100 liver transplant patients with HCV recurrence underwent interferon-free SOF-based treatment. A total of 51 patients received SOF/ LDV with or without RBV. Twenty-nine HCV genotype 1 or 4 patients with histologically proven stage 0-2 fibrosis were treated with SOF/ LDV for 12 weeks; another 22 patients with advanced fibrosis (stage 3-4) either received SOF/ LDV plus weight-adjusted RBV or prolonged treatment for 24 weeks. Results End of treatment response and sustained virological response ( SVR) were achieved in 100% of the 51 patients, irrespective of the treatment group. Patients with prolonged treatment duration or with RBV developed significantly more adverse events ( AEs) compared to the SOF/ LDV group: 19 (86.4%) vs 8 (27.6%), P<.001. One of the predominant and most relevant AEs was the development of anemia in 43.1% of 10 patients receiving RBV, which was a significant result ( P<.001). RBV co-medication had to be reduced in 11 (55%) patients and then stopped in 8 (40%) patients because of AEs. No significant difference was observed among the groups regarding kidney function. Conclusion The SOF/ LDV combination is a reliable therapy of recurrent HCV infection after LT. It is easy to administer and to achieve SVR in immunocompromised patients without interactions with immunosuppressive medications. Considering the high rate of AEs, frequent discontinuation of RBV treatment, and the 100% SVR, the use of RBV as co-medication in a 12-week SOF/ LDV regimen does not seem to be justified after LT. [ABSTRACT FROM AUTHOR]

Background & Aims Several studies have shown that new direct-acting antivirals maintain their efficacy in liver transplant ( LT) recipients with severe hepatitis C virus ( HCV) recurrence. We determined the clinical impact of sofosbuvir/ribavirin in LT through the changes in liver function and fibrosis state at 24 and 48 weeks after treatment. Methods Between June 2014 and July 2015, 126 patients (30 F3, 96 F4 Metavir stage) were enrolled to receive sofosbuvir + ribavirin (24 weeks, 118 patients) or sofosbuvir + simeprevir + ribavirin (12 weeks, 8 patients); treatment was initiated at a median time of 4.3 years from LT. Median follow-up after therapy completion was 461 days. Results All 30 F3 patients achieved a sustained virological response at week 24 after treatment ( SVR24) and showed a distinct amelioration of the AST-to-platelet ratio index ( APRI), FIB-4 and liver stiffness at elastography by week 24 post-therapy, which were maintained at week 48. Of the 96 F4 cirrhotic patients, 72 (75%) achieved SVR24 accompanied by significant improvement of liver function, which was maintained at week 48 (Child B-C 22% baseline, 11% week 24, 7% week 48); APRI, FIB-4 and liver stiffness further improved significantly between weeks 24 and 48 of follow-up. Among the 77 responders (27 F3, 50 F4) who underwent elastography at baseline and at the end of follow-up, 39 (50.6%; 18 F3, 21 F4) exhibited a regression in fibrosis stage. Conclusion At about 1 year from the completion of successful sofosbuvir-based therapy, patients with post- LT HCV and severe fibrosis experienced a long-term liver function improvement accompanied by a regression of fibrosis stage in half of them. [ABSTRACT FROM AUTHOR]

Introduction. Hepatitis C virus genotype 4 is predominant in the Middle East and Northern Africa, even if it has recently spread to Southern Europe. Data about the treatment of post-liver transplantation (LT) genotype 4 hepatitis C recurrence are scarce. We report a retrospective analysis of post-LT genotype 4 hepatitis C treatment in 9 Italian transplant centres, focusing on the overall survival rates and treatment outcome.Results. Among 452 recipients, we identified 17 HCV genotype 4 patients (16 males, 1 female) transplanted between 1998 and 2007. All patients received combined antiviral treatment with conventional doses of interferon (recombinant or pegylated) and ribavirin after histological diagnosis of hepatitis C recurrence. The observed overall survival after LT was 100% at 1 year and 83.3% at 5 years. More than 1/3 (35.3%) of patients achieved a sustained virological response (SVR) and 40% (data available in 15 subjects) an early virological response (EVR), which was significantly associated with the achievement of SVR (overall accuracy: 85.7%; predictive values of EVR absence/presence 80/88.8%; chi-square p < 0.05).Conclusion. In conclusion, in post-LT genotype 4 hepatitis C treatment, SVR rates are similar to genotype 1. Patients who don’t show an EVR are not likely to achieve a SVR.

It has been 4 years since the first, long-term (> 3 years) prospective comparison of adult-to-adult living donor liver transplantation (A2ALLTx) to adult deceased donor liver transplantation (ADDLTx) was reported.1 In this follow up, prospective, IRB approved, 10-year comparison of A2ALLTx to ADDLTx we expand on our initial observations. This data includes: age, gender, ethnicity, primary liver disease, waiting time, pretrans-plant CTP/MELD score, cold ischemia time (CIT), perioperative mortality, acute and chronic rejection, graft and patient survival, charges and post-transplant complications.In 10 years, 465 ADDLTx (81.37) and 107 A2ALLTx (18.7%) were performed at VCUHS. Hepatitis C virus (HCV) was the most common reason for transplantation in both groups (54.5% vs. 48.2%). Data regarding overall patient and graft survival and retransplantation rates were similar. Comparison of patient/graft survivals, retransplantation rates in patients with and without HCV were not statistically different. A2ALLTx patients had less acute rejection (9.6% vs. 21.7%) and more biliary complications (27.1% vs. 17.6%).In conclusion, A2ALLTx is as durable a liver replacement technique as the ADDLTx. Patients with A2ALLTx were younger, had lower MELD scores, less acute rejection and similar histological HCV recurrence. Biliary complications were more common in A2ALLTx but were not associated with increased graft loss compared to ADDLTx.

HLA and IL-28B genes were independently associated with severity of HCV-related liver disease. We investigated the effects of these combined genetic factors on post-transplant survival in HCV-infected recipients, aiming to provide new data to define the optimal timing of novel antiviral therapies in the transplant setting. HLA-A/B/ DRB1 alleles and IL-28B rs12979860 (C > T) polymorphism frequencies were determined in 449 HCV viremic recipients and in their donors. Median follow-up was 10 years; study outcome was graft survival. HLA- DRB1*11 phenotype and IL-28B C/C genotype were significantly less frequent in recipients than donors (27.8% vs. 45.9% and 27.4% vs. 44.9%, respectively, P < 0.00001). Ten-year graft survival was better in patients with HLA- DRB1*11 ( P = 0.0183) or IL-28B C/C ( P = 0.0436). Conversely, concomitant absence of HLA- DRB1*11 and IL-28B C/C in 228 (50.8%) predicted worse survival ( P = 0.0006), which was already evident at the first post-transplant year ( P = 0.0370). In multivariable Cox analysis, absence of both markers ranked second as risk factor for survival ( HR = 1.74), following donor age ≥ 70 years ( HR = 1.77). In the current era of direct-acting antiviral agents, the negative effects of this common immunogenetic profile in HCV-infected recipients could be most effectively neutralized by peri-transplant treatment. This should be particularly relevant in countries where elderly donors represent an unavoidable resource. [ABSTRACT FROM AUTHOR]

The hepatitis C virus (HCV) infects more than 180 million people globally, with increasing incidence, especially in developing countries. HCV infection frequently progresses to liver cirrhosis leading to liver transplantation or death, and HCV recurrence still constitutes a major challenge for the transplant team. Antiviral therapy is the only available instrument to slow down this process, although its actual impact on liver histology, in responders and nonresponders, is still controversial. We are now facing a 'new era' of direct antiviral agents that is already changing the approach to HCV burden both in the pre- and in the post-liver transplantation settings. Available data on sofosbuvir/ledipasvir and sofosbuvir/simeprevir in patients with decompensated cirrhosis sustain a SVR12 of 89% , but one-third of patients do not clinically improved. The sofosbuvir/ribavirin treatment in stable cirrhotic patients with HCC before liver transplantation is associated with 2% recurrence rate if liver transplantation is performed at least one month after undetectable HCV-RNA is achieved. The treatment of recurrence with the new antiviral drugs is associated with a SVR that ranges between 60 and 90%. In this review, we have focused on the evolution of antiviral therapy for HCV recurrence from the 'old' interferon-based therapy to the 'new' interferon-free regimens, highlighting useful information to aid the transplant hepatologist in the clinical practice. [ABSTRACT FROM AUTHOR]

Background: Silibinin has been shown to have anti-HCV activity and immune-modulating properties by regulating dendritic cell (DC) function. DCs are antigen-presenting cells that, together with regulatory T cells (Treg), play a pivotal role in controlling alloimmune, as well as anti-HCV immune responses. Methods: Twelve liver transplant patients with HCV recurrence received iv infusion of Silibinin (iv-SIL) for 14 consecutive days. Using flow cytometry, before and at the end of treatment, we determined the frequencies of circulating myeloid (m) and plasmacytoid (p) DC and Treg and the expression of costimulatory/coregulatory molecules by the DC subsets and Treg. Statistical analysis was performed using the paired Student's t test and Pearson correlation test. Results: After iv-SIL treatment, we observed an elevated plasmacytoid dendritic cell (pDC)/myeloid dendritic cell (mDC) ratio, while pDC displayed lower HLA-DR and higher immunoglobulin-like transcript 4 (ILT4), CD39, and HLA-G expression compared to the pretreatment baseline. In addition, after iv-SIL, mDC showed increased inducible costimulator ligand (ICOSL) expression. No changes were detected in Treg frequency or programed death (PD)-1 expression by these cells. Moreover, several correlations between DC/Treg markers and clinical parameters were detected. Conclusions: This descriptive study, in liver transplant patients with HCV recurrence, reveals the impact of iv-SIL on DC and Treg. The changes observed in circulating pDC and mDC that have previously been associated with tolerogenic conditions shed new light on how iv-SIL may regulate anti-viral and alloimmunity. We have also observed multiple clinical correlations that could improve the clinical management of liver transplant patients and that deserve further analysis. [ABSTRACT FROM AUTHOR]

Interferon-based regimens with first-generation protease inhibitors have a limited efficacy and an unfavorable safety profile. Combination therapies with two or more second-generation direct-acting antivirals plus/minus ribavirin revolutionized treatment strategies in patients chronically infected with hepatitis C virus. In this rapidly evolving era, patients in the transplant setting benefit from interferon-free treatment regimens. Scientific societies can barely keep up with this development, making it necessary to update the clinical guidelines by the American and European Associations for the Study of Liver Diseases within short periods. This review presents and discusses the currently available data of the use of interferon-free treatment in the setting of liver transplantation. However, costs, different reimbursement strategies, and health-care options cannot be answered by guidelines and recommendations from scientific societies. Further investigator-initiated trials are needed to individualize treatment concepts. [ABSTRACT FROM AUTHOR]

Background Female gender has been reported to be a risk factor for graft loss after liver transplantation for hepatitis C virus (HCV)-related cirrhosis but evidence is limited to retrospective studies. Aims To investigate the impact of recipient gender and donor/recipient gender mismatch on graft outcome. Methods We performed a survival analysis of a cohort of 1530 first adult transplants enrolled consecutively in Italy between 2007 and 2009 and followed prospectively. After excluding possible confounding factors (fulminant hepatitis, human immunodeficiency virus co-infection, non-viremic anti-HCV positive subjects), a total of 1394 transplant recipients (604 HCV-positive and 790 HCV-negative) were included. Results Five-year graft survival was significantly reduced in HCV-positive patients (64% vs 76%, p = 0.0002); Cox analysis identified recipient female gender (HR = 1.44, 95% CI 1.03–2.00, p = 0.0319), Mayo clinic End stage Liver Disease score (every 10 units, HR = 1.25, 95% CI 1.03–1.50; p = 0.022), portal thrombosis (HR = 2.40, 95% CI 1.20–4.79, p = 0.0134) and donor age (every 10 years, HR = 1.14, 95% CI 1.05–1.24, p = 0.0024) as independent determinants of graft loss. All additional mortality observed among female recipients was attributable to severe HCV recurrence. Conclusions. This study unequivocally shows that recipient female gender unfavourably affects the outcome of HCV-infected liver grafts. [ABSTRACT FROM AUTHOR]

Background: Recurrent hepatitis C infection after liver transplantation (LT) is associated with lower rates of graft and patient survival. Methods: Here we describe the first use of daclatasvir, simeprevir, and ribavirin (RBV) as an all-oral triple regimen administered to 6 liver transplant recipients with recurrent hepatitis C, one with GT 1a and 5 with GT 1b. All patients were treated for 24 weeks. Trough levels of immunosuppression, laboratory measures, and potential adverse effects were closely monitored. Results: For all patients, viral load became undetectable between treatment weeks 4 and 12. One patient experienced a viral breakthrough at the 10th week of treatment; this was associated with the selection of resistance-associated variants (D168Y in NS3 and ΔP32 in NS5A). For the other 5 patients, end-of-treatment response and for 4 patients SVR24 was achieved. Viremia recurred in one patient 4 weeks after the end of treatment, which was again associated with the selection of resistance-associated variants (D168V in NS3 and ΔP32 in NS5A). Clinical measures of liver function improved substantially for all patients. Adverse events were few and limited to moderate anemia caused by RBV. Importantly, adjustments to the immunosuppressant dosage were not required. Conclusions: The described regimen appears to be safe and effective for liver transplant patients and will be a promising treatment regimen for post-LT patients. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Despite improvement on outcomes post liver transplantation (LT), complications such as HCV recurrence (HCV-rec) and acute cellular rejection (ACR) continue to be a challenge for transplant physicians. Accurate diagnostic tools to better dissect between those complications post-LT are crucial for prompt and correct diagnosis and treatment. It is well known that the overlapping features of clinical and histo-pathological characteristics between these conditions turn difficult the appropriate differential diagnosis. Recently, new technological advances had supported the field of biomarker discovery in many diseases. Disease biomarkers capable to differentiate ACR versus HCV-rec post-LT is a long waited task in the transplant community. This editorial describes and discusses potential biomarkers of disease differentiation including recent reports in the field of genomics, proteomics, immunohistochemistry among other technologies. [ABSTRACT FROM AUTHOR]

Background & Aims: Protease inhibitors (PI) with peginterferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge. Methods: This cohort study included 37 liver transplant recipients (male, 92%, age 57±11years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage ⩾F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%). Results: Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p =0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p =0.125). A sustained virological response 12weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p =0.24). Treatment was discontinued in sixteen patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8±1.1-fold and 3.4±1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2±1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir. Conclusions: Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring. [ABSTRACT FROM AUTHOR]

Abstract: It has been demonstrated that sustained virological response (SVR) in patients with chronic hepatitis C indicates resolution of infection. We describe a late hepatitis C virus (HCV) relapse with nearly identical HCV genotype 1a RNA, 14 months after a SVR achievement following a 12-month pegylated-interferon plus ribavirin treatment in a human immunodeficiency virus (HIV) infected patient. This virological relapse occurred concomitantly with interruption of highly active antiretroviral therapy and subsequent increased immunosuppression. HCV retreatment was successful and HCV RNA was undetectable at 50 months of follow-up. This case suggests that late relapse of HCV infection in HIV-positive patients with SVR is possible in case of increased immunodeficiency related to highly active antiretroviral therapy interruption. In such circumstances, a close monitoring of HCV viremia and aminotransferases should be performed. [Copyright &y& Elsevier]

Survival outcomes for liver retransplantation ( LRTx) after graft loss in HCV patients ( HCV- LRTx) are generally considered inferior to those after non- HCV- LRTx. Between January 1, 2005 and June 30, 2011, our center performed 663 LTx, including 116 (17.5%) LRTx, 41 (35.3%) of which were more than 90 d after the LTx. Twenty-nine (70.7%) LRTx were performed in HCV antibody-positive individuals. We compared patient demographics, baseline characteristics and outcomes of our HCV- LRTx group with the HCV- LRTx patients from the most recent OPTN database covering the same time period. Our Kaplan-Meier HCV- LRTx one-, three-, and five-yr HCV- LRTx patient survival rates were 86.2%, 79.0%, and 72.4%, respectively compared with the OPTN one-, three-, and five-yr HCV- LRTx survival rates of 73.3%, 59.0%, and 51.3% respectively. Likewise, our graft survival rates were higher than OPTN rates at all time points studied. We performed a higher percentage of HCV- LRTx as simultaneous liver/kidney transplants ( SLK) (37.9% vs. 21.8%) and recorded shorter warm (30 ± 4 vs. 45 ± 23 min) and cold ischemic times (5:44 ± 1:53 vs. 7:36 ± 3:12 h:min). Conclusion: In our experience, HCV- LRTx patient and graft survival rates are comparable to LTx survival rates and are higher than the rates described by OPTN. [ABSTRACT FROM AUTHOR]

Abstract: Background: While the role of serum HCV RNA quantitation in hepatitis C virus recurrence after liver transplantation is well established, the meaning of HCV RNA tissue quantitation is largely unclear, and no correlations with recipient outcome have been investigated yet. Aims: To assess the predictive value, and a possible prognostic role, of tissue and serum HCV RNA in first post-transplant biopsies. Methods: We retrospectively reviewed the first post-transplant biopsies of 83 recipients. Tissue and serum HCV RNA was quantitated by RT-PCR, and compared with serum, clinical and histological data. Results: HCV RNA quantitation allowed us to categorise recipients into three different risk groups: (1) tissue HCV RNA≤1.5IU/ng with any serum HCV RNA; (2) tissue HCV RNA>1.5IU/ng and serum HCV RNA<40×106 copies/mL; (3) tissue HCV RNA>1.5IU/ng and serum HCV RNA≥40×106 copies/mL. Hepatitis C virus recurrence rates in the three groups were 68%, 91% and 100% (P =0.004); hepatitis C virus-related mortality was 0%, 14% and 45% respectively (P <0.001). Conclusions: This preliminary study on serum and tissue HCV RNA quantitation allows recipient “stratification” in prognostic groups, which could be applicable in the future for timely antiviral treatment and/or immunosuppression modulation. [Copyright &y& Elsevier]

Background & Aims: Reinfection of the graft is the rule in patients with HCV cirrhosis undergoing liver transplantation, and HCV-RNA reaches pre-transplantation levels within the first month. Short-term intravenous silibinin monotherapy is safe and shows a potent in vivo anti-HCV effect. We aimed at evaluating the safety and antiviral effect of prolonged intravenous silibinin, started immediately before liver transplantation. Methods: Single centre, prospective, pilot study, to assess the safety and effect on HCV-RNA kinetics during at least 21days of intravenous silibinin monotherapy (20mg/kg/day) in 9 consecutive HCV genotype 1 subjects, in comparison to a control, non-treated group of 7 consecutive prior transplanted subjects under the same immunosuppressive regimen (basiliximab, steroids, delayed tacrolimus, micophenolate). Results: Intravenous silibinin led to significant, maintained and progressive HCV-RNA decreases (mean HCV-RNA drop at week 3, −4.1±1.3log10 IU/ml), and lack of viral breakthrough during administration. Four patients (44%) reached negative HCV-RNA, maintained during silibinin treatment, vs. none in the control group, but HCV-RNA relapsed in all of them after a median of 21days (16–28), following silibinin withdrawal. Partial responders to silibinin showed marked decreases in HCV-RNA when compared to controls, but lower than complete responders. There were no clinical adverse effects, and silibinin led to asymptomatic transient hyperbilirubinemia (week 2, 4.2±2.2 vs. 2.5±3.6mg/dl; p =0.02). Conclusions: Prolonged intravenous silibinin monotherapy was safe in the immediate liver transplantation period, leading to a potent and time dependent antiviral effect and lack of HCV-RNA breakthrough during administration. However, HCV-RNA rebounded after withdrawal, and silibinin monotherapy did not avoid reinfection of the graft. [ABSTRACT FROM AUTHOR]

We report herein the 10-year outcome of the Tor Vergata weaning off immunosuppression protocol in hepatitis C virus ( HCV) liver transplant patients. Thirty-four patients who had received a liver graft for HCV-related cirrhosis were enrolled in a prospective study in which they were progressively weaned off immunosuppression. The primary endpoints were feasibility and safety of the weaning; the second aim was to assess fibrosis progression. At the 10-year follow-up, of the eight original tolerant patients, six remained IS-free. Of the 26 individuals who could not be weaned, 22 were alive. When the baseline biopsies were compared with the 10-year biopsies, the tolerant group showed no differences in staging, whereas the nontolerant group showed a significant increase in staging. The fibrosis progression rates calculated for the tolerant and the nontolerant groups were −0.06 ± 0.12 and 0.1 ± 0.2, respectively ( P = 0.04). Furthermore, with the last taken biopsies, nine nontolerant patients were showing frank cirrhosis versus no cirrhosis among the tolerant patients. After a 10-year follow-up of a Tor Vergata weaning protocol, 6/34 patients completed follow-up without reinstitution of immunosuppression and this appeared beneficial regarding a reduction in fibrosis progression. [ABSTRACT FROM AUTHOR]

HCV-related cirrhosis represents the leading indication for liver transplantation in the Western countries. HCV reinfection after liver transplantation occurs in virtually all patients transplanted for HCV-related liver disease Histological evidence of chronic HCV infection develops in 50 to 90 % of patients by 12 months after liver transplantation, and cirrhosis occurs in about 20 % of patients within 5 years after transplant. Several studies have evaluated host, viral, and transplant-related factors that might be associated with the severity of HCV recurrence. Among host factors, immunosuppression is one of the major factors that accounts for accelerated HCV recurrence and it has been an area of extensive research and controversy. Donor age, steatosis, and immunogenetic factors are also relevant in determining the outcome in patients transplanted for HCV-related cirrhosis. A major step to prevent complications of HCV recurrence related to the rapid fibrosis is the posttransplant antiviral treatment. Two strategies have been tried: pre-emptive or other strategies as soon as possible after liver transplantation or elective therapy once there is histological evidence of recurrent hepatitis C. Retransplantation due to graft failure from recurrent hepatitis C is rarely an option in the era of organ shortage as it is associated with poor outcome, but many case needs to be considered early in the evolution of disease. New antivirals may change the outcome dramatically of patients transplanted for HCV cirrhosis. [ABSTRACT FROM AUTHOR]

Abstract: Background and aims: The management of patients treated for hepatitis C recurrence after liver transplantation and not achieving virological response following treatment with interferon plus ribavirin is controversial. Methods: A retrospective analysis of the outcomes of 70 patients non-responders to antiviral treatment after liver transplantation was performed. Twenty-one patients (30.0%; Group A) were treated for ≤12 months and 49 (70.0%; Group B) for more than 12 months. Results: The 2 groups were comparable for main demographic, clinical and pathological variables. Median duration of antiviral treatment was 8.2 months in Group A and 33.4 months in Group B. No patient achieved a complete virological response. The 5-year patient hepatitis C-related survival rate was 49.2% in Group A and 88.3% in Group B (P =0.002), while the 5-year graft survival rate was 49.2% in Group A and 85.9% in Group B (P =0.007). The median yearly fibrosis progression rate was 1.21 per year in Group A and 0.40 per year in Group B (P =0.001). Conclusions: Prolonged antiviral treatment showed an overall beneficial effect in transplanted patients with a recurrent hepatitis C infection and not responding to conventional therapy. The treatment should be continued as long as it is permitted, in order to improve clinical and histological outcomes. [Copyright &y& Elsevier]

Abstract: Hepatitis C virus (HCV) infection is the most common indication for liver transplantation and the major cause of graft failure. A widely used immunosuppressant, cyclosporine A (CsA), for people who receive organ transplantation, has been recognized to have the ability to inhibit HCV replication both in vivo and in vitro. In this study, we investigated the effects of several other immunosuppressants, including mycophenolate mofetil (MMF), rapamycin and FK506, on HCV replication in human hepatic cells. MMF treatment of hepatic cells before or during HCV infection significantly suppressed full cycle viral replication, as evidenced by decreased expression of HCV RNA, protein and production of infectious virus. In contrast, rapamycin and FK506 had little effect on HCV replication. Investigation of the mechanism(s) disclosed that the inhibition of HCV replication by MMF was mainly due to its depletion of guanosine, a purine nucleoside crucial for synthesis of guanosine triphosphate, which is required for HCV RNA replication. The supplement of exogenous guanosine could reverse most of anti-HCV effect of mycophenolate mofetil. These data indicate that MMF, through the depletion of guanosine, inhibits full cycle HCV JFH-1 replication in human hepatic cells. It is of interest to further determine whether MMF is indeed beneficial for HCV-infected transplant recipients in future clinical studies. [Copyright &y& Elsevier]

HCV-related disease is the most common indication for liver transplantation (LT). HCV recurrence, which is almost universal, has a significant impact on patient and graft survival after LT and still represents a great unsolved issue for the liver transplant community. Several treatment strategies have been proposed. Since antiviral therapy has limited efficacy and can be administrated only in selected transplant recipients and additionally that immunosuppressive drugs have a negative impact on HCV re-infection, the achievement of an immunosuppression-free state after LT could play a central role in the avoidance of rapid HCV recurrence. [ABSTRACT FROM AUTHOR]

Abstract: There is in vitro proof that mTOR proteins play a role in protecting HCV infected cells from apoptosis. The aim of this cohort study was to evaluate the effect of sirolimus as an mTOR inhibitor on hepatitis C recurrence in liver transplant recipients. Hepatitis C virus positive patients were followed prospectively regarding transaminases, immunosuppressive target levels, HCV RNA and influence of donor and recipient factors on viral recurrence and survival. Viral recurrence was defined as elevated liver enzymes combined with active hepatitis diagnosed on the basis of increasing viral load and/or biopsy-proven HCV relapse in the transplanted organ. Sixty-seven HCV positive patients were included: 39 received a regimen including sirolimus; 28 patients received calcineurin inhibitors. Sirolimus patients showed a significant decrease in the HCV PCR levels (p <0.05). Survival of the sirolimus patients was significantly higher (p <0.03) than in the other patient cohort. Sirolimus has been shown to be a potent immunosuppressive agent after liver transplantation, though nothing is known about its effect on HCV. This analysis suggests that sirolimus has potential to suppress viral recurrence in HCV positive liver transplant candidates. [Copyright &y& Elsevier]

Bárcena R, Moreno A, Foruny JR, Blázquez J, Graus J, Riesco JM, Blesa C, García-Hoz F, Sánchez J, Gil-Grande L, Nuño J, Fortún J, Rodriguez-Sagrado MA, Moreno A. Partial splenic embolization and peg-IFN plus RBV in liver transplanted patients with hepatitis C recurrence: safety, efficacy and long-term outcome. Clin Transplant 2010: 24: 366–374. © 2009 John Wiley & Sons A/S. There is limited information on the long-term outcome in liver transplant (LT) subjects undergoing partial splenic embolization (PSE) prior to full dose pegylated interferon/ribavirin (peg-IFN/RBV). Methods: Retrospective review of eight LT subjects after PSE and antiviral therapy. Results: Baseline platelets and neutrophils were <50 000 cells/mL and <1000 cells/mL in 75% and 50%. Mean splenic infarction volume was 85 ± 13%. PSE produced major complications in three (37.5%): recurrent sterile netrophilic ascites and renal insufficiency (n = 2), and splenic abscess (n = 1). Full-dose peg-IFN/RBV was started in seven (87.5%), with two early withdrawals (28.6%) despite early virological response (toxicity and infection); both subjects died. Anemia led to RBV dose-adjustment in six (86%), with human recombinant erythropoietin (EPO) use in four (57%). No peg-IFN adjustments or granulocyte-colonies stimulating factor were needed. Two patients reached sustained virological response (SVR) (28.6%). Two non-responders maintained prolonged therapy with biochemical/histological improvement. After a median follow-up of 151 wk, we observed significant improvements in hematological parameters, aspartate aminotransferase, alanine aminotransferase, international normalized ratio, and prothrombin activity. Conclusions: Extensive PSE after LT produced significant morbidity (37.5%). Peg-IFN/RBV was completed in five out of seven (71%), with SVR in two (28.6%). RBV adjustement due to anemia was high despite EPO use. Only patients able to complete or maintain antiviral therapy survived, with long-term significant benefits in hematological parameters and liver function tests. [ABSTRACT FROM AUTHOR]

Background/Aims: Liver transplantation (LT) in immune-suppressed human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected patients is feasible but raises questions regarding the severity of HCV recurrence on the liver graft and preservation of immune function. We investigated whether LT is deleterious to the immune system. Methods: Fourteen HIV–HCV coinfected patients (HIV viral load [VL] <50copies/ml; median CD4 count of 276/mm3 pretransplantation) were grafted for HCV–cirrhosis and followed over 2years. Nine patients received anti-HCV therapy post-transplantation. HCV and HIV VLs and degree of acute and chronic hepatitis were monitored. Peripheral blood T-cell phenotypes and interferon-γ (IFN-γ) immune responses against opportunistic pathogens, HCV, and HIV-1 p24 were evaluated. Results: Median HCV VLs, CD4 counts, T-cell subsets, and IFN-γ–producing T-cell frequencies against opportunistic pathogens and HIV-1 p24 did not change over time. HCV-specific T cells were observed ex vivo in two patients pretransplantation and in two others post-transplantation. HCV-specific in vitro amplification enabled the detection of HCV-specific IFN-γ-producing responses in three further patients post-transplantation. Anti-HCV responses were observed independently of anti-HCV therapy and were undetectable in patients with severe hepatitis or liver fibrosis. Conclusions: These results demonstrate that LT in HIV–HCV coinfected patients is not deleterious to the immune system and does not alter immune responses directed against HCV, HIV, or opportunistic pathogens. [Copyright &y& Elsevier]

Background: We report the update of the Tor Vergata immunosuppression (IS) weaning protocol in stable hepatitis C virus (HCV) liver transplant (LT) recipients. Methods: The weaning off IS was attempted in 34 patients who had received a LT 63.5 ± 20.1months earlier, for HCV-related end stage liver disease. Patients were observed over a period of 6.5years. During this time, yearly protocol liver biopsies were performed. Primary endpoints were determined as the feasibility of weaning off IS and its impact on the long term disease progression. Secondary endpoints were defined as the impact on patient morbidity and quality of life. Results: Of the 8 originally tolerant patients, 7 remain alive and in good condition, while 1 died of severe HCV recurrence 10years post-LT and 6years after complete removal of IS. Four out of 26 intolerant individuals died of HCV recurrence (2×), lung carcinoma (1×) and acute myocardial infarction (1×), after a mean follow up period from LT of 115 (range 100-124). The 10-year survival from LT was comparable (89% vs. 87.5%). Liver graft pathology showed no significant differences between the two groups in terms of staging, fibrosis progression rate, and grading. Quantitative HCV RNA assay showed a significant non-logarithmic difference between the two groups (p = 0.03). The two groups were comparable in terms of liver function tests and lipid profile, whereas they differed with regards to glycaemia. While all tolerant individuals were euglicemic, 11 intolerant individuals developed new onset diabetes that required specific treatment (p = 0.03). Finally, significantly more intolerant patients are suffering from either cardiovascular (14/22 vs. 0/7, p = 0.01) or infectious diseases (13/22 vs. 0/7, p = 0.01). Conclusions: After a 6.5-year follow up, the complete withdrawal of IS in HCV LT recipient remains safe and beneficial to patients, because it reduces the IS-related morbidity and increases the quality of life. The impact on HCV disease recurrence is less marked than after 3.5years. [ABSTRACT FROM AUTHOR]

Aim of the work: To compare between different available regimens of DAAs (sofosbuvir/daclatasvir and sofosbuvir/ledipasvir) regarding the efficacy and safety for treatment of compensated recurrent hepatitis C Virus infection after liver transplantation in Egyptian patients and to study the correlation between sofosbuvir / daclatasvir and sofosbuvir / ledipasvir and post-transplant complications. Background: Liver transplantation is the only curative treatment for ESLD and HCC. Liver disease resulting from chronic HCV infection is the leading indication for liver transplantation. For patients with detectable HCV-RNA levels at the time of transplantation, postoperative recurrence of HCV infection was "immediate and universal." Recurrent HCV infection follows an aggressive course and retransplantation frequently is associated with a poor outcome. Patients and Methods: This prospective study was conducted on recipients, who underwent living donor liver transplantation in Ain Shams Center for Organ Transplantation (ASCOT) at Ain Shams University Specialized Hospital (ASUSH), Cairo, Egypt between June, 2016 and May, 2017. Data of the recipients, who underwent living donor liver transplantation during the study period, were reviewed and the patients who fulfilled the inclusion criteria were enrolled into this study. The patients who fulfilled the inclusion criteria and received antiviral treatment were followed up monthly during their treatment and after finishing treatment for at least 3 months. Results: Treatment of HCV recurrence in liver transplant recipients with SOFþDCVþRBV or SOF/LDVþRBV seems to confer high rates of SVR. There was no difference between both regimens regarding adverse events. Prolonged treatment of HCV recurrence after LDLT (24 weeks) was significantly associated with a higher SVR (P = 0.035). Conclusion: Adding RBV to antiviral regimens in the treatment of HCV recurrence in liver transplant recipients doesn't seem to add to the efficacy of DAAs. Adherence to prolonged course of antiviral treatment (6 months) when treating HCV recurrence post liver transplantation seems to be associated with higher rates of SVR than shorter course (3 months) with no increase in the incidence of adverse events or rejection episodes. [ABSTRACT FROM AUTHOR]

Background/Aims: As life expectancy in HIV–HCV co-infected patients improves, end stage liver disease requiring liver transplantation (LT) may become an emerging problem. We report the Paul Brousse Hospital experience of transplantation for end stage cirrhosis in HIV–HCV co-infected patients. Methods: Seven consecutive HIV–HCV co-infected patients were transplanted between December 1999 and December 2002 for end stage liver disease due to HCV. All patients were treated by highly active antiretroviral therapy (HAART), HIV plasma viral load was <400copies/ml and median CD4 lymphocyte count was 306cells/mm3 (range, 103–510) before LT. At the time of evaluation (March 2003), the median follow-up was 21 months (range, 4–40). Results: Two patients died, 4 and 22 months, respectively after LT. At the last biopsy, METAVIR score was staged F4 in two patients, F3 in two, and F1 in one. Microvesicular steatosis was noted in nearly all patients. The ratio of mitochondrial to nuclear DNA was low in three of four patients examined as compared with the amount of liver mtDNA found in eight HIV-negative, HCV-infected controls (P=0.01). Conclusions: A significant defect in the activity of the respiratory chain complex IV was noted in all five patients studied. Mitochondrial hepatotoxicity and severe HCV recurrence occur in HIV–HCV co-infected patients after LT. [Copyright &y& Elsevier]