Hepatitis C Virus Recipients Research Articles

Use of liver grafts from donation after cardiac death donors for recipients with hepatitis C virus

Hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation in the United States. Although studies have addressed the use of expanded criteria donor organs in HCV(+) patients, to date the use of liver grafts from donation after cardiac death (DCD) donors in HCV(+) patients has been addressed by only a limited number of studies. This retrospective analysis was undertaken to study the outcomes of DCD liver grafts used in HCV(+) recipients. Seventy-seven HCV(+) patients who received DCD liver grafts were compared to 77 matched HCV(+) patients who received donation after brain death (DBD) liver grafts and 77 unmatched non-HCV patients who received DCD liver grafts. There were no differences in 1-, 3-, and 5-year patient or graft survival among the groups. Multivariate analysis showed that the Model for End-Stage Liver Disease score [hazard ratio (HR) = 1.037, 95% confidence interval (CI) = 1.006-1.069, P = 0.018] and posttransplant cytomegalovirus infection (HR = 3.367, 95% CI = 1.493-7.593, P = 0.003) were significant factors for graft loss. A comparison of the HCV(+) groups for fibrosis progression based on protocol biopsy samples up to 5 years post-transplant did not show any difference; in multivariate analysis, HCV genotype 1 was the only factor that affected progression to stage 2 fibrosis (genotype 1 versus non-1 genotypes: HR = 2.739, 95% CI = 1.047-7.143, P = 0.040). In conclusion, this match-controlled, retrospective analysis demonstrates that DCD liver graft utilization does not cause untoward effects on disease progression or patient and graft survival in comparison with DBD liver grafts in HCV(+) patients.

The clinical consequences of utilizing donation after cardiac death liver grafts into hepatitis C recipients

Chronic liver failure from hepatitis C virus (HCV) remains the leading indication for liver transplantation (LT). Donation after cardiac death (DCD) donors are becoming a more frequent source of liver grafts. Hepatitis C recipients of standard donation after brain death (DBD) allografts may have inferior long-term results, and more so when expanded criteria organs are used. Given the nature of DCD grafts, a focus on the consequences to HCV recipients is of major importance. We analyzed the graft outcomes in HCV and non-HCV liver transplant recipients of DCD grafts. 21 patients underwent LT using a DCD grafts (9 HCV, 12 non-HCV) the donor body mass index and age was similar in both groups. One non-HCV recipient was retransplanted for primary non-function (PNF 8%). Biliary complications occurred in 22% (2/9) of the HCV group, 50% (6/12) in the non-HCV group (p=0.21). After a mean of 19months follow up, excellent patient and graft survival was seen in the non-HCV recipients of DCD grafts (100 and 92%, respectively). These outcomes were numerically less in HCV recipients (78, 67%). In the HCV recipients of DCD grafts, 33% (3/9) suffered graft loss, two from fatal aggressive fibrosing cholestatic (FCH) HCV and one due to ischemic cholangiopathy. Although a statistically significant difference in patient/graft survival for HCV and non-HCV recipients of DCD organs was not shown, it is clear that more dire consequences exist for HCV recipients of DCD grafts, highlighting the need for larger data sets for evaluating this patient population.

A case report of recurrence of mixed cryoglobulinemic glomerulonephritis in a renal transplant recipient

Recurrence of glomerulonephritis (GN) is one of the major risk factors of long-surviving renal graft dysfunction. Cryoglobulinemic glomerulonephritis of hepatitis-C virus (HCV)-negative patient is a rare cause of end-stage renal disease. There is little case report of recurrent cryoglobulinemic glomerulonephritis in negative HCV recipients after renal transplantation. We represent a renal allograft recipient of an interesting recurrent cryoglobulinemic glomerulonephritis. The patient was diagnosed with mixed cryoglobulinemic glomerulonephritis by kidney biopsy at the age of 32 . He had no HCV, HBV nor liver dysfunction. He received immunosuppressive therapy, however, was introduced to hemodialysis treatment after 13 yr. He received a cadaveric renal transplantation at the age of 50, and immunosuppressive treatment was started with ciclosporin, prednisolone and mycophenolate mofetil (MMF). Four yr after transplantation, he developed fever and purpura of lower limbs. His serum creatinine level did not increase, however, proteinuria, hematuria, hypocomplementemia, positive rheumatoid factor and mixed cryoglobulinemia were noted. Detailed analysis failed to reveal the composition of mixed cryoglobulinemia. The renal allograft biopsy showed membranoproliferative-type GN with monocyte and polynuclear leukocyte accumulation of capillary loops and small cellular crescent. Immunofluorescent study showed C3, IgG and IgM deposition of mesangial and capillary pattern. Regardless of steroid pulse therapy, hypocomplementemia and positive rheumatoid factor did not improve. Ten yr after transplantation, he was affected by cellulitis and sepsis. Afterward, rising of serum creatinine and nephrotic range proteinuria developed. The allograft biopsy revealed advanced cryoglobulinemic glomerulonephritis with characteristic vascular lesions. Electron microscopy showed organized subendothelial deposits compatible with cryoglobulinemic glomerulonephritis and proteinaceous thrombus in arteriole.

Liver Transplantation for Hepatitis C Viral Infection in Children: An Analysis of the UNOS Experience in Comparison to Adults

Introduction: While end-stage liver disease from Hepatitis C Virus (HCV) is the leading indication for orthotopic liver transplantation (OLT) for adults in the US, it rarely leads to transplantation in children. Furthermore, HCV infection in the pediatric population follows a unique course. Very little data exists, however, regarding liver transplantation for children with HCV Aims: 1) Compare graft and patient survival in pediatric versus adult HCV transplant recipients. 2) Determine the impact of re-transplantation for recurrent disease on patient and graft survival in children. 3) Identify independent risk factors associated with worsened graft and patient survival in the pediatric HCV liver transplant recipients. Methods: The United Network for Organ Sharing (UNOS) database of liver transplant recipients from September 30, 1987 through February 20, 2009 was queried. Patients receiving OLT for HCV associated liver disease (acute hepatic failure and cirrhosis) were selected. Patients with any comorbid liver disease were excluded. Children in this group were defined as 21 or younger at transplant. Graft and patient survival were calculated via the Kaplan-Meier method, with comparison between groups made by log-rank test. The relative impact of risk factors on graft and patient survival were calculated using a Cox Regression model. All statistical computations were performed with SPSS version 15.0 (Chicago, Illinois). Results: A total of 18,961 first-time OLT's were performed for HCV-associated liver disease (94 pediatric, 18,867 adult). Of these, 941 patients were re-transplanted for recurrence: 18 children (19.1%) vs. 923 adults (4.9%). Children experienced significantly shorter graft survival after first transplant in comparison to adults (2792 days vs. 3346 days mean survival, p=0.045). Mean patient survival was, however, similar between the two groups after first transplant (4196 vs 3816 days, p=0.468). Re-transplantation did not adversely impact graft or patient survival in the pediatric HCV recipients. Mean graft survival was 2792, 1873, and 1500 days, after first, second, and third transplants, respectively (p=0.847-0.996). Mean patient survival was 4196, 1982, and 1499 days after first, second, and third time transplants (p=0.197-0.921). No independent risk factors for worsened patient or graft survival were identified by Cox regression. Conclusions: While pediatric OLT recipients with HCV have worsened graft survival in comparison to their adult counterparts, patient survival is similar. Furthermore, re-transplantation for recurrent disease in children is a safe option not associated with worsened graft or patient survival. Further study is necessary to identify risk factors for OLT in this population.

Impact of the donor risk index on the outcome of hepatitis C virus-positive liver transplant recipients

We have investigated the impact of the donor risk index (DRI) on the outcome of hepatitis C virus (HCV)-infected patients undergoing liver transplantation (LTx). Retrospective analysis was performed from the Organ Procurement and Transplantation Network database (January 1, 2000 to June, 2006). The DRI was calculated as described by Feng et al. (Am J Transplant 2006;6:783-790). Model for End-Stage Liver Disease (MELD) exceptions were excluded from the analysis. Relative risk (RR) estimates of patient and graft loss were derived from Cox regression models. The Wald test was used to test the effect of the MELD score at transplant on the HCV-DRI interaction. Of the LTx recipients (16,678), 76.1% were Caucasian, and 66.7% were male; the median age was 52 (range, 18-80 years), and the mean follow-up time was 1148 days (range, 0-2959 days). Forty-six percent (n = 7675) of LTx recipients were HCV(+). The median DRI was 1.3 (range, 0.77-4.27). Increasing DRI was associated with a statistically significant increase in the RR of graft failure and patient death for both HCV(+) and HCV(-) recipients. However, HCV(+) recipients demonstrated a significantly higher increase in the RR of patient and graft loss as a function of the DRI than HCV(-) subjects, even after adjustments for several recipient factors, including MELD. In conclusion, a synergistic interaction between donor DRI and recipient HCV status exists, such that an allograft from a high-DRI donor more adversely affects the outcome of an HCV(+) recipient than that of an HCV(-) recipient.

Long‐term outcomes of donation after cardiac death liver allografts from a single center

Organ shortage continues to be a major challenge in transplantation. Recent experience with controlled non-heart-beating or donation after cardiac death (DCD) are encouraging. However, long-term outcomes of DCD liver allografts are limited. In this study, we present outcomes of 19 DCD liver allografts with follow-up >4.5 years. During 1998-2001, 19 (4.1%) liver transplants (LT) with DCD allografts were performed at our center. Conventional heart-beating donors included 234 standard criteria donors (SCD) and 214 extended criteria donors (ECD). We found that DCD allografts had equivalent rates of primary non-function and biliary complications as compared with SCD and ECD. The overall one-, two-, and five-yr DCD graft and patient survival was 73.7%, 68.4%, and 63.2%, and 89.5%, 89.5%, and 89.5%, respectively. DCD graft survival was similar to graft survival of SCD and ECD in non hepatitis C virus (HCV) recipients (p > 0.370). In contrast, DCD graft survival was significantly reduced in HCV recipients (p = 0.007). In conclusion, DCD liver allografts are durable and have acceptable long-term outcomes. Further research is required to assess the impact of HCV on DCD allograft survival.

A Novel Immunosuppressive Strategy Combined with Preemptive Antiviral Therapy Improves the Eighteen-Month Mortality in HCV Recipients Transplanted with Aged Livers

Donor's age and immunosuppression influence the severity of hepatitis C virus (HCV) recurrence. We analyzed the 18-month mortality in 302 consecutive HCV recipients, divided into three groups, with homogeneous immunosuppression and preemptive antiviral therapy in the last group. Group 1: one hundred thirty-three patients (1996-2000) mainly received a triple therapy (steroids- cyclosporine A [CyA]-azathioprine); first line treatment of biopsy-proven acute rejection (BPAR) was with steroid boluses; second-line with OKT3. Group 2: ninety-one patients (2001-2003) mainly received a double therapy (steroids-CyA) and induction with anti-CD25 antibody; first-line BPAR treatment was increased dose/switch of the calcineurin inhibitor; second-line steroid boluses; third-line extracorporeal photopheresis (ECP). Group 3: seventy-eight patients (2004-June 2006) mainly received a monotherapy (CyA) associated with ECP and induction with anti-CD25 antibody; first-line BPAR treatment was increased dose/switch of calcineurin inhibitor with increased ECP frequency, second-line steroid boluses, and third-line retransplantation. Median donor's age increased from 54 (13-84) years in group 1 to 60 (10-93) years in group 2 and 66 (17-84) years in group 3 (P<0.001). Overall mortality in groups 1, 2, and 3 decreased from 28.6% to 22% and 10.2% respectively (P = 0.003); HCV-related mortality from 7.5% and 12.1% to 1.3%, respectively (P = 0.029). BPAR were 33.8% in group 1 and 9.0% in group 3. Applicability of the preemptive antiviral therapy in group 3 was 69.2%. Sustained viral clearance occurred in 38.9% of 36 patients who completed the protocol. At multivariate analysis, a single-drug immunosuppressive regimen was the only variable independently associated with survival (P=0.05). Low and steady immunosuppression combined with preemptive antiviral therapy significantly improved the short-term mortality of HCV recipients transplanted with aged organs. Prolonged follow-up will assess whether this benefit is maintained in the long run.

Impact of donor graft steatosis on overall outcome and viral recurrence after liver transplantation for hepatitis C virus cirrhosis

The aim of this study was to determine the influence of donor graft steatosis on overall outcome, viral recurrence, and fibrosis progression in orthotopic liver transplantation (OLT) for hepatitis C virus (HCV) cirrhosis. One hundred twenty patients who underwent OLT for HCV cirrhosis between 1995 and 2005 were included in the study. Donor steatosis was categorized as absent (0%-10%; n = 40), mild (10%-30%; n = 32), moderate (30%-60%; n = 29), or severe (>60%; n = 19). A Cox multivariate analysis for marginal donor variables and a Model for End-Stage Liver Disease index were performed. Fibrosis evolution was analyzed in liver biopsies (fibrosis < 2 or > or =2) 3, 6, and 12 months post-OLT and in the late post-OLT period. Fifty-six grafts were lost (46%). The survival of the grafts was inversely proportional to donor liver steatosis: 82%, 72%, and 72% at 1, 2, and 3 years post-OLT in the absence of steatosis; 73%, 63%, and 58% with mild steatosis; 74%, 62%, and 43% with moderate steatosis; and 62%, 49%, and 42% with severe steatosis (P = 0.012). HCV recurrence was earlier and more frequent in recipients with steatosis > 30% (46% versus 32% at 3 months, P = 0.017; 58% versus 43% at 6 months, P = 0.020; 70% versus 56% at 12 months, P = 0.058; and 95% versus 69% at 3 years post-OLT, P = 0.0001). Graft survival was lower in alcoholic liver disease recipients versus HCV recipients when steatosis was >30% at 3, 6, and 12 months post-OLT (P = 0.042) but not when steatosis was <30% (P = 0.53). A higher fibrosis score was obtained 3 months post-OLT (P = 0.033), 6 months post-OLT (P = 0.306), 12 months post-OLT (P = 0.035), and in the late post-OLT period (P = 0.009). In conclusion, donor graft steatosis influences the outcome of OLT for HCV cirrhosis. HCV recurrence is more frequent and earlier in recipients of moderately and severely steatotic livers. Fibrosis evolution is higher when graft steatosis is >30%. OLT with >30% steatotic donor livers should be precluded in HCV recipients.

Impact of Donor Age on the Results of Liver Transplantation in Hepatitis C Virus-Positive Recipients

Objective Hepatitis C virus (HCV)-cirrhosis is the most frequent indication for orthotopic liver transplantation (OLT) among adults in most European and American transplant centers. The aim of this study was to analyze the impact of donor age on graft survival among HCV-positive cirrhotic transplant patients. Materials and Methods We performed an observational, retrospective study between March 1997 and December 2004, analyzing 340 liver transplantations. The patients were divided into 4 groups, considering whether the HCV infection was the indication for OLT and whether the age of the donor was older or younger than 48 years: group 1 (HCV, <48 years); group 2 (HCV, >48 years); group 3 (non-HCV, <48 years); and group 4 (non-HCV, >48 years). Results A univariate analysis showed that posttransplantation graft survival was clearly influenced by recipient HCV serologic status ( P = .018). However, no graft survival differences were found when the analysis variable was age (>48 or <48 years). When both variables were studied, a positive HCV serology did not modify graft survival when the donor age was <48 years ( P = .32), but had a statistically significant negative impact when the age was >48 years ( P = .02). Conclusions The use of older donors for HCV recipients resulted in worse graft and patient survivals in our study. This difference in survival was not present in non-HCV recipients or when grafts for HCV recipients were procured from younger donors. Donor age <30 years was a protective factor for graft survival among HCV recipients.

Might rapid virological response be used as a stopping rule in liver transplant recipients treated with pegylated interferon plus ribavirin?

We read with interest the article by Hanouneh et al.1 on the prediction of pegylated interferon plus ribavirin (P/R) response in liver transplant (LT) recipients with histologically proven recurrent hepatitis C. As highlighted by the authors, the management of problematic patients such as graft recipients can be eased by early kinetics of hepatitis C virus (HCV), that is, HCV-RNA clearance at week 4 [rapid virological response (RVR)] and a 2-log drop of HCV-RNA at week 12 [early virological response (EVR)], which predict treatment outcome. However, although in LT patients EVR has an absolute negative predictive value (NPV) for P/R treatment outcome,1-4 the NPV and positive predictive value (PPV) of RVR are far from being absolute, even in non-LT patients. We were therefore surprised by Hanouneh et al.'s findings of RVR having 100% PPV and 88% NPV in LT patients receiving P/R. We think that the RVR accuracy discrepancies between this study and other studies4, 5 might reflect differences in the performance of the studies; for example, many patients (38%) in the present series were not tested for serum HCV-RNA at week 4 of treatment. We treated with P/R 46 patients transplanted for end-stage HCV with inclusion criteria similar to those investigated by Hanouneh et al.1 The treatment was intended for 48 weeks, being independent of the genotype or virological response to either peginterferon alfa-2a or peginterferon alfa-2b weekly, whereas the ribavirin dosing was less than that in Hanouneh et al.'s study (400–600 versus 1000–1200 mg/day). Serum HCV-RNA levels were assessed at baseline and at 4 weeks, 12 weeks, 48 weeks, and 6 months after the completion of therapy, and most patients received growth factors. The 2 cohorts were similar for clinicovirological features but differed in terms of the prevalence of non-Caucasians and body mass index (lower in our cohort). Cyclosporine A (CSA)–based immunosuppression was higher in our patients than in the American cohort (48% versus 17%). The rates of SVR were 41% and 35%, respectively, with a preference for genotypes 2 and 3 in both (76% versus 87%). The SVR rates in the 2 cohorts are in line with those reported by recent studies on P/R-treated HCV recipients ranging from 30% to 45%.6 In our patients, RVR had 86% PPV and 78% NPV (see Table 1), that is, midway between the data of Hanouneh et al.1 and other data.3 The results indicate that RVR is a good predictor of treatment outcome in LT patients with recurrent hepatitis C; however, it is not accurate enough to become a stopping rule of P/R therapy. In our cohort, CSA-based immunosuppression was independently associated with SVR in multivariate analysis (odds ratio = 6.65, 95% confidence interval = 1.79–24.7, P < 0.005), and this supports the synergic anti-HCV effect of CSA and interferon already demonstrated in vitro and in vivo.5 This was not investigated by Hanouneh et al. because the majority of their patients received tacrolimus-based immunosuppression. The higher dose of ribavirin in the American patients with respect to ours might have been beneficial in terms of SVR, too.6 Maria Francesca Donato*, Francesca Agnelli*, Cristina Rigamonti*, Eliana Arosio*, Massimo Colombo*, * First Division of Gastroenterology, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Ospedale Maggiore, Policlinico, Mangiagalli e Regina Elena, Milan, Italy.

Correlation Between Liver Fibrosis and Inflammation in Patients Transplanted for HCV Liver Disease

Hepatitis C virus (HCV) re-infection after liver transplantation (LT) is characterized by an accelerated disease progression in recent years with unclear mechanisms. We evaluate the relationship between progression of liver fibrosis and histological necro-inflammation in HCV recipients, according to age of transplant. Fifty-five patients transplanted (1993-2002) for HCV liver disease, were included in the study. Recipients were retrospectively stratified in three different age of transplant, of 40 months each: group 1) from January 1993 to May 1996; group 2) from June 1996 to august 1999; group 3) from September 1999 to December 2002. Grading (necro-inflammation) and staging (fibrosis) scores were evaluated in liver biopsies at 1, 2 and 3 years from LT (Ishak classification). For all age of transplant the main factor associated with fibrosis progression, was grading score (p < 0.05). However mean staging score for each point of grading increased from 0.3 +/- 0.2 in older LT to 0.7 +/- 0.5 in newer ones (p = 0.01). In conclusion in HCV-LT patients (1) liver fibrosis is strictly associated to histological necro-inflammation; (2) the proportion of this relationship has been changing in recent years since newer LT patients, show an increased amount of fibrosis in comparison with the older ones, for similar grading score.

Revisiting Posttransplant Survival for Hepatitis C Virus Recipients

Hepatitis C virus (HCV) is the most frequent indication for adult liver transplantation in Europe and United States. Posttransplantation HCV recurrence is universal and previous studies have reported a reduced survival in comparison to non-HCV recipients. We report the findings of a comparative survival analysis of adult recipients (n=12,434) with HCV from two eras using the United Network for Organ Sharing database. Cox regression modeling was used to compare both eras (A: 1994-1998 and B: 1999-2003). The 1-, 3-, and 5-year adjusted graft survivals for era A (n=5,215) and era B (n=7,519) were 80%, 69%, and 62% versus 84%, 72%, and 64%, respectively (P<0.001), whereas the 1-, 3-, and 5-year adjusted patient survivals were 86%, 77%, and 70% for era A versus 87%, 78%, and 70% for era B, respectively (P=0.79). This comparative analysis of posttransplant outcomes for HCV recipients suggests an improvement in graft survival in the latter years.

Contribution of Marginal Donors to Liver Transplantation for Hepatitis C Virus Infection

The use of marginal liver donors can affect the outcomes of liver transplantation in patients with hepatitis C virus (HCV) infection. There are no firm conclusions about which donor criteria are important for allocation of high-risk grafts to recipients with HCV cirrhosis. We performed 120 consecutive liver transplantations for HCV infection between 1995 and 2005. Marginal donor criteria were considered to be: age >70 years, macrovesicular steatosis >30%, moderate-to-severe liver preservation injury, high inotropic drug dose (dopamine >15 μg/kg/min; epinephrine, norepinephrine, or dobutamine at any doses), peak serum sodium >155 mEq/L, any hypotensive episode <60 mm Hg and >1 hour, cold ischemia time >12 hours, ICU hospitalization >4 days, bilirubin >2 mg/dL, AST and/or ALT >200 UI/dL. Graft survival with donors showing these marginal criteria was compared with optimal donors using Kaplan-Meier analysis and the log-rank test. Independent predictors of survival were computed with the Cox proportional hazards model. Fifty-six grafts (46%) were lost during follow-up irrespective of the Model for End-Stage Liver Disease (MELD) scores of the recipients in each category. Upon univariate analysis, grafts with moderate-to-severe steatosis ( P = .012), those with severe liver preservation injury ( P = .007) and prolonged cold ischemia time ( P = .0001) showed a dismal prognosis at 1, 3, and 5 years. Upon multivariate analysis, fat content ( P = .0076; OR = 4.2) and cold ischemia time >12 hours ( P = .034; OR = 7.001) were independent predictors of graft survival. Among HCV recipients, marginal liver donors worked similar to those from “good” donors, except for those with fatty livers >30%, especially when combined with a prolonged cold ischemia time.

Hepatitis C Virus Seropositivity in Organ Donors and Survival in Heart Transplant Recipients

Although liberalization of donor criteria could expand the donor pool, the use of certain "marginal donors," such as those who are hepatitis C virus (HCV) positive, is controversial. Little is known about the effect of donor HCV positivity on survival in cardiac transplantation. To examine the association between donor HCV positivity and survival among heart transplant recipients and to determine the effects of recipient age and recipient HCV status on this association. A multicenter cohort study was performed using the US Scientific Registry of Transplant Recipients. Adult heart transplant patients who received their transplants between April 1, 1994, and July 31, 2003, were eligible for inclusion. All-cause mortality. Of 10 915 patients meeting entry criteria, 261 received an HCV-positive donor heart. Mortality was higher among recipients of HCV-positive donor hearts at 1 year (16.9% vs 8.2%; P<.001), 5 years (41.8% vs 18.5%; P<.001), and 10 years (50.6% vs 24.3%; P<.001). Using Kaplan-Meier methods, 1-, 5-, and 10-year survival rates were 83%, 53%, and 25%, and 92%, 77%, and 53% for recipients of HCV-positive and HCV-negative donor hearts, respectively (P<.001, log-rank test). Recipients of HCV-positive donor hearts were more likely to die of liver disease and coronary vasculopathy. After propensity matching, the overall hazard ratio (HR) associated with receipt of an HCV-positive donor heart was 2.10 (95% confidence interval [CI], 1.60-2.75). Stratified analyses showed that HRs did not vary by recipient HCV status or by recipient age (for recipients aged 18-39 years: HR, 1.75 [95% CI, 0.70-4.40]; for recipients aged 40-59 years: HR, 2.23 [95% CI, 1.42-3.52]; and for recipients aged 60 years and older: HR, 2.07 [95% CI, 1.32-3.27]; overall P value for interaction, >.10). Receipt of a heart from an HCV-positive donor is associated with decreased survival in heart transplant recipients. This association appears to be independent of recipient HCV status and age. Preferential allocation of HCV-positive donors to HCV-positive recipients and/or older recipients is not warranted.

Impact of donor age on survival and fibrosis progression in patients with hepatitis C undergoing liver transplantation using HCV+ allografts

Studies have suggested that the use of hepatitis C virus (HCV)-positive (HCV+) donor allografts has no impact on survival. However, no studies have examined the effect that HCV+ donor histology has upon recipient and graft survival. We evaluated the clinical outcome and impact of histological features in HCV patients transplanted using HCV+ livers. We reviewed all patients transplanted for HCV at our institution from 1988 to 2004; 39 received HCV+ allografts and 580 received HCV-negative (HCV-) allografts. Survival curves compared graft and patient survival. Each HCV+ allograft was stringently matched to a control of HCV- graft recipients. No significant difference in survival was noted between recipients of HCV+ livers and controls. Patients receiving HCV+ allografts from older donors (age > or =50 yr) had higher rates of graft failure (hazard ratio, 2.74) and death rates (hazard ratio, 2.63) compared to HCV- allograft recipients receiving similarly-aged older donor livers. Matched case-control analysis revealed that recipients of HCV+ allografts had more severe fibrosis post-liver transplantation than recipients of HCV- livers (P = 0.008). More advanced fibrosis was observed in HCV+ grafts from older donors compared to HCV+ grafts from younger donors (P = 0.012). In conclusion, recipients of HCV+ grafts from older donors have higher rates of death and graft failure, and develop more extensive fibrosis than HCV- graft recipients from older donors. Recipients of HCV+ grafts, regardless of donor age, develop more advanced liver fibrosis than recipients of HCV- grafts.

Survival Outcome After Hepatic Retransplantation for Hepatitis C Virus–Positive and –Negative Recipients

Introduction Hepatitis C virus (HCV)–related liver disease is the most common indication for liver transplantation in the United States. Recurrence of HCV infection in these recipients is almost uniform. The currently available antiviral treatment is known to cause significant side effects, and the rate of sustained viral response is low. There is still controversy about whether such patients should undergo subsequent transplantations for HCV disease. This study compared outcomes for hepatic retransplantation performed in HCV(+) and HCV(−) recipients at a single center. Patients and methods From December 1994 through November 2003, 68 patients at our institution received a second liver allograft. Nineteen of the recipients were HCV(+) (group A) and 49 were HCV(−) (group B). All patients were followed until January 2004. The mean follow-up time after initial retransplantation was 37 ± 29 months. Patient and graft survival for the two groups were compared. Results Seven recipients in group A (36.8%) and 22 recipients in group B (44.9%) died during follow-up. The actuarial 3-year patient survival after initial retransplantation for groups A and B were 61.7% and 51.6%, respectively. Nine patients required a second retransplantation, 3 (15.8%) in group A and 6 (12.2%) in group B. The actuarial 3-year graft survival from initial retransplantation for groups A and B were 56.3% and 45.7%, respectively. Conclusion We observed slightly better patient and graft survivals at 3 years from initial retransplantation in HCV(+) recipients compared to HCV(−) recipients. This may be due to younger donor age and better selection of HCV(+) recipients in this series.

Use of Hepatitis B Core Antibody–Positive Liver Allograft in Hepatitis C Virus–Positive and –Negative Recipients With Use of Short Course of Hepatitis B Immunoglobulin and Lamivudine

Introduction With the shortage of donor organs, increasing number of hepatitis B core antibody (HBcAb)–positive [HBcAb(+)] liver allografts are being used for liver transplantation (LTx) in patients who are HBcab-negative [HBsAb(−)]. This study was aimed at assessing outcomes for hepatitis C virus (HCV)-positive [HCV(+)] and HCV-negative [HCV(−)] patients who received HBcAb(+) liver grafts from deceased donors and also received a short course of hepatitis B immunoglobulin (HBIg) with long-term lamivudine therapy after LTx. Materials and methods From February 1995 through February 2003, 28 patients (mean age 53.8 ± 10.2 years, 19 men and nine women, 16 HCV[−]; 12 HCV[+]) received HbcAb(+) liver allografts. All recipients received a short course of HBIg prophylaxis (10,000 units/day for 4 days) and long-term lamivudine 100 mg/d after LTx in addition to a tacrolimus-based immunosuppressive regimen. Results Seven (25%) of the 28 recipients died during follow-up and three recipients required retransplantation. Three recipients (10.7%) developed HBV infection during follow-up, one of whom died 36 months after LTx and the other two had YMDD mutant HBV. The overall 6-year actuarial patient survival after transplantation was 74.4% and those for HCV(−) and HCV(+) recipients were 81.3% and 66.6%, respectively ( P = .46). The overall 6-year actuarial graft survival was 63.9% and those for HCV(+) and HCV(−) recipients were 68.8% and 57.1%, respectively ( P = .6). Conclusion We conclude that HBcAb(+) liver grafts can be used for both HCV(+) patients and HCV(−) patients who are critically ill, have early hepatocellular carcinoma, or have been exposed to HBV in the past. A short course of HBIg-lamivudine combination therapy provides effective prophylaxis against HBV infection in 89% of recipients of HBcAb(+) grafts.

Response to 'Viral Hepatitis Guidelines for Transplant Recipients'

Response to 'Viral Hepatitis Guidelines for Transplant Recipients'

Liver transplantation with hepatitis C virus-infected graft: Interaction between donor and recipient viral strains

Superinfection of different viral strains within a single host provides an opportunity for studying host-virus and virus-virus interactions, including viral interference and genetic recombination, which cannot be studied in infections with single viral strains. Hepatitis C virus (HCV) is a positive single-strand RNA virus that establishes persistent infection in as many as 85% of infected individuals. However, there are few reports regarding coinfection or superinfection of HCV. Because of the lack of tissue culture systems and small animal models supporting efficient HCV replication, we explored these issues in the setting of liver transplantation where both recipient and donor were infected with different HCV strains and therefore represent a distinct model for HCV superinfection. Serial serum samples collected at multiple time points were obtained from 6 HCV-positive liver donor/recipient pairs from the National Institute of Diabetes and Digestive and Kidney Diseases liver transplantation database. At each time point, HCV genotype was determined by both restriction fragment length polymorphism analysis and phylogenetic analysis. Furthermore, we selectively sequenced 3 full-length HCV isolates at the earliest time points after liver transplantation, including both 5′ and 3′ ends. Detailed genetic analyses showed that only one strain of HCV could be identified at each time point in all 6 cases. Recipient HCV strains took over in 3 cases, whereas donor HCV strains dominated after liver transplantation in the remaining 3 cases. In conclusion, in all 6 cases studied, there was no genetic recombination detected among HCV quasispecies or between donor and recipient HCV strains. (H epatology 2003;38:25-33.)

The impact of advancing donor age on histologic recurrence of hepatitis C infection: The perils of ignored maternal advice

Recurrent hepatitis occurs in the majority of patients undergoing liver transplantation for hepatitis C virus (HCV) cirrhosis, with progression to cirrhosis in up to 30% after 5 years. Based on these data, a decrease in survival can be anticipated with prolonged follow-up. Furthermore, posttransplantation HCV-fibrosis progression has been shown in recent years to increase. Our aims were (1) to describe the natural history of HCV-infected recipients, particularly to determine whether survival has decreased in recent years; (2) to compare this outcome with that observed in non-HCV-infected cirrhosis controls; and (3) to determine the factors associated with disease severity and survival. Among 522 cirrhotic patients undergoing transplantation between 1991 and 2000, 283 (54%) were infected with HCV. Yearly biopsies were performed in these recipients and at 1 and 5 years in the remainder. With similar follow-up, the percentage of deaths in the HCV(+) group was signifi cantly higher than in the HCV-group (37% vs. 22%, P <.001), and patient survival was lower (77%, 61%, 55% vs. 87%, 76%, 70% at 1, 5, and 7 years, respectively; P =.0001). Although survival has increased in the HCV- group in recent years, it has significantly decreased in HCV recipients (P <.0001). The main cause of death among the latter was decompensated graft cirrhosis (n = 23/105, 22%), whereas that of HCV-patients was infections (n = 10/52, 19%). Reasons for the recent worse outcome in HCV+ recipients include the increased donor age and stronger immunosuppression. In conclusion, patient survival is lower among HCV+ recipients than among HCV- ones and has been decreasing in recent years. The aging of donors is a major contributor to this worse outcome.Background and Aim: Cirrhosis with liver failure due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT). Reinfection of the transplanted liver by HCV is inevitable, and aggressive hepatitis with accelerated progression to graft cirrhosis may be observed. Of concern, recent reports suggest that the outcome of LT for HCV may have deteriorated in recent years. Determinants of rate of progression to cirrhosis in the immunocompetent non-transplant patient are well defined, and the most powerful determinant is patient age at the time of infection. Following LT for HCV, recipient age does not affect outcome of HCV reinfection. However, the impact of donor age on graft fibrosis progression rate following LT has not been examined. Methods: We have examined post-transplant biopsies to assess histological activity, including fibrosis stage (scored 0-6 units, 6 representing established cirrhosis), and to calculate fibrosis progression rates in 101 post-transplant specimens from 56 HCV infected LT patients. Univariate and multivariate analyses examined the impact of parameters including recipient and donor age and sex on fibrosis progression rate, and on predicted time to cirrhosis. Results: For the cohort, median fibrosis progression rate was 0.78 units/year, and median interval from transplantation to development of cirrhosis was 7.7 years. In multivariate analysis, donor age (not recipient age) was a powerful determinant (P = 0.02) of fibrosis progression rate. When the liver donor was younger than 40 years, median progression rate was 0.6 units/year and interval to cirrhosis was 10 years. When the donor was aged 50 years or more, median progression rate was 2.7 units/year and interval to cirrhosis only 2.2 years. During the observation period there has been a significant increase in donor age (P = 0.01) but date of transplantation per se is not a determinant of progression rate when included in multivariate analyses. Conclusions: Donor age has a major influence on graft outcome following transplantation for HCV. The changing organ donor profile will affect the long term results of LT for HCV. These observations have important implications for donor liver allocation.