Predictors of graft and patient survival in hepatitis C virus (HCV) recipients: model to predict HCV cirrhosis after liver transplantation

BACKGROUND: Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is almost universal, but the natural history of recurrent HCV in the allograft is highly variable. Our study had two aims: 1) to assess the impact of different pre- and postLT factors on graft and patient survival in HCV transplant recipients and 2) to create a model which may predict the patients at risk for HCV-related graft cirrhosis at 5 years postLT. METHODS: A total of 168 LTs were considered for this study. Univariate and multivariate Cox proportional hazards regression model was used, as well as logistic regression analysis to create a model of prediction of HCV cirrhosis within 5 years after LT. RESULTS: Predictive factors for both decreased graft and patient survival included patients recently transplanted (2000-2004), induction without azathioprine, short-term therapy with mycophenolate mofetil and prednisone (< or =6 months), presence of early cholestasis, histologically proven early recurrence of hepatitis C. Recipient human leukocyte antigen DR3 positivity, presence of early cholestasis, and donor age >50 years were identified as independent predictors of graft cirrhosis within 5 years. A predictive model was established in order to calculate at 6 months a risk score for graft HCV cirrhosis within 5 years postLT using a formula that included the identified independent predictors. The area under receiver operating characteristic curve was 0.83, indicating a good ability to predict medium-term HCV allograft cirrhosis. CONCLUSION: This model may be a useful tool for better identifying high-risk HCV patients who should be selected for early initiation of antiviral therapy.     

Prospective study of liver transplant recipients with HCV infection: evidence for a causal relationship between HCV and insulin resistance.

An association between hepatitis C virus (HCV) infection and insulin resistance (IR) has been recently reported. However, causality has not been established. The cross-sectional nature of most reported studies and varying degrees of fibrosis have limited definitive conclusions about the independent role of HCV in development of IR. We sought to evaluate whether HCV induces IR by prospectively analyzing a cohort of adult liver transplant (LT) recipients. A total of 34 adults (14 HCV(+) and 20 HCV(-)) who underwent consecutive LT were followed during the first year posttransplantation. IR was estimated using the homeostasis model assessment (HOMA). Univariate and multivariate repeated measures analyses and Cox regression models were used. There were no significant differences between the groups with respect to age, body mass index (BMI), family history of diabetes, alcohol consumption, or laboratory indices. The cohort had no or minimal fibrosis. There was lower prednisone use in the HCV(+) group, and no difference in the use of tacrolimus between the two groups was found. IR was 77% higher in HCV(+) subjects during the first year post-LT when controlling for BMI (P = 0.035). Subjects with high HCV ribonucleic acid (RNA) levels reached high HOMA-IR significantly earlier than those with lower HCV RNA (P = 0.03). Following the first month post-LT, HCV(+) subjects were 4 times more likely to become diabetic than HCV(-) controls (P < 0.01). In conclusion, there is significantly higher IR in the HCV(+) group during the first year post-LT. This cannot be explained by differences in BMI, medications used, alcohol consumption, or degree of fibrosis. Higher HCV RNA levels were associated with earlier elevations in HOMA-IR. Collectively, these results provide strong evidence that HCV induces the development of IR.     

Balancing donor and recipient risk factors in liver transplantation: the value of D-MELD with particular reference to HCV recipients

Donor-recipient match is a matter of debate in liver transplantation. D-MELD (donor age × recipient biochemical model for end-stage liver disease [MELD]) and other factors were analyzed on a national Italian database recording 5946 liver transplants. Primary endpoint was to determine factors predictive of 3-year patient survival. D-MELD cutoff predictive of 5-year patient survival <50% (5yrsPS<50%) was investigated. A prognosis calculator was implemented (http://www.D-MELD.com). Differences among D-MELD deciles allowed their regrouping into three D-MELD classes (A < 338, B 338-1628, C >1628). At 3 years, the odds ratio (OR) for death was 2.03 (95% confidence interval [CI], 1.44-2.85) in D-MELD class C versus B. The OR was 0.40 (95% CI, 0.24-0.66) in class A versus class B. Other predictors were hepatitis C virus (HCV; OR = 1.42; 95% CI, 1.11-1.81), hepatitis B virus (HBV; OR = 0.69; 95% CI, 0.51-0.93), retransplant (OR = 1.82; 95% CI, 1.16-2.87) and low-volume center (OR = 1.48; 95% CI, 1.11-1.99). Cox regressions up to 90 months confirmed results. The hazard ratio was 1.97 (95% CI, 1.59-2.43) for D-MELD class C versus class B and 0.42 (95% CI, 0.29-0.60) for D-MELD class A versus class B. Recipient age, HCV, HBV and retransplant were also significant. The 5yrsPS<50% cutoff was identified only in HCV patients (D-MELD ≥ 1750). The innovative approach offered by D-MELD and covariates is helpful in predicting outcome after liver transplantation, especially in HCV recipients.     

Outcomes of liver transplantation in HIV-infected individuals: the impact of HCV and HBV infection.

Liver transplantation (LT) in human immunodeficiency virus (HIV)-positive individuals is considered to be an experimental therapy with limited reported worldwide experience, and little long-term survival data. Published data suggest that the short-term outcome is encouraging in selected patients. Here, we report our experience in 14 HIV-infected liver allograft recipients, and compare outcomes between those coinfected with hepatitis C virus (HCV) and the non-HCV group. A total of 14 HIV-infected patients (12 male, 2 female, age range 26-59 years) underwent LT between January 1995 and April 2003. Indications for LT were HCV (n = 7), hepatitis B virus (HBV; n = 4), alcohol-induced liver disease (n = 2), and seronegative hepatitis (n = 1); 3 patients presented with acute liver failure. At LT, CD4 cell counts (T-helper cells that are targets for HIV) ranged from 124 to 500 cells/microL (mean 264), and HIV viral loads from <50 to 197,000 copies/mL. Nine of 12 patients were exposed to highly active antiretroviral therapy (HAART) before LT. In the non-HCV group (n = 7), all patients are alive, all surviving more than 365 days (range 668-2,661 days). No patient has experienced HBV recurrence, and graft function is normal in all 7 patients. However, 5 of 7 HCV-infected patients died after LT at 95-784 days (median 161 days). A total of 4 patients died of complications due to recurrent HCV infection and sepsis, despite antiviral therapy in 3 of them. A total of 3 patients experienced complications relating to HAART therapy. In conclusion, outcome of LT in HIV-infected patients with HBV or other causes of chronic liver disease indicates that LT is an acceptable therapeutic option in selected patients. However, longer follow-up in larger series is required before a conclusive directive can be provided for HCV / HIV coinfected patients requiring LT.     

Prevalence of new-onset diabetes mellitus in Brazilian liver transplant recipients: association with HCV infection

New-onset diabetes melittus (NODM) is a serious complication following transplantation. Recent studies suggest an association between hepatitis C virus (HCV) infection and DM both in nontransplant settings as well as after liver transplantation (LT). The aim of this study was to assess the prevalence of NODM among Brazilian LT recipients, analyzing possible risk factors including HCV infection. We conducted a cross-sectional study to evaluate the prevalence of NODM in 82 LT recipients with a posttransplant follow-up > or =1 year including 29 HCV-positive patients and 53 with other causes for liver disease. Patients were considered to meet the criteria for DM if they had two consecutive fasting glucose values > or =126 mg/dL or if they were taking insulin or oral hypoglycemic agents at the time of the study. The overall prevalence of NODM was 18.29% with a median interval of 20 months between LT and diagnosis of DM. The age, sex, and race distribution, immunosuppressive regimen, number of rejection episodes treated with pulse therapy, and family history of DM were similar in both groups. However, the frequency of BMI > or = 30 in the pre- and posttransplant periods was higher among patients who developed NODM (P = .02). Upon multivariate analysis of the entire cohort, HCV infection was the only significant predictor of NODM (OR = 4.31, CI = 1.17 to 15.84, P = .02). In conclusion, our study confirmed an association between HCV infection and NODM among Brazilian liver transplant recipients, suggesting that HCV infection may have a potential role in the pathogenesis of posttransplantation DM.     

Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis.

A controversy exists over whether the outcome of a hepatitis C virus (HCV)-infection-related liver transplant differs based on the calcineurin inhibitor (CNI) used. We have performed a systematic review and a subsequent meta-analysis evaluating tacrolimus (Tac)-based vs. cyclosporine A-based immunosuppression in HCV-infected liver transplant recipients. Searches were conducted to locate randomized controlled trials comparing Tac vs. cyclosporine A. Data on HCV liver transplant recipients were obtained, independently of whether the study was specifically designed for patients with this disease or not. A fixed effects model was used for statistical pooling of the relative risks (RR) for the different outcomes. A total of 5 articles (366 patients) fulfilled the inclusion criteria. Statistically significant differences between Tac-based vs. cyclosporine A-based therapies were not found for mortality (P = 0.11; RR = 0.72; 95% confidence interval [CI], 0.49-1.08), graft survival (P = 0.37; RR = 0.86; 95% CI, 0.61-1.21), biopsy-proven acute rejection (P = 0.65; RR = 0.91; 95% CI, 0.61-1.36), corticoresistant acute rejection (P = 0.26; RR = 2.25; 95% CI, 0.55-9.29), and fibrosing cholestatic hepatitis (P = 0.92; RR = 0.96; 95% CI, 0.41-2.26). In 1 study, no differences were detected regarding severe fibrosis at 1 yr. In conclusion, patient and graft survivals in HCV-positive liver transplant patients are similar independently of the CNI selected as basic immunosuppressant. Unfortunately, data on the severity of recurrence and effect on viremia are scarce. Well-designed randomized prospective studies are needed to determine whether there are differences between the 2 CNIs regarding these specific variables.     

肝功能衰竭患者肝移植后并发肺炎的危险因素分析

目的 探讨和分析肝功能衰竭患者肝移植后并发肺炎的危险因素.方法 回顾性分析2004年9月至2006年12月80例肝功能衰竭肝移植患者的临床资料.将80例患者分为肺炎组和对照组,应用多因素分析寻找肝功能衰竭患者肝移植后并发肺炎的独立危险因素.结果 肺炎组27例,死亡13例,对照组53例,死亡5例.多因素分析显示肝移植后发生肺炎与患者死亡密切相关(OR=14.857,95%的可信区间为3.703～59.612,P=0.0001).与发牛肺炎密切相关的因素有:年龄(OR=1.976,95%的可信区间为1.090～3.582,P=0.0249)、肝肾综合征(OR=5.266,95%的可信区间为0.912～30.414,P=0.0634)以及移植肝功能不良(OR=91.997,95%的可信区间为19.000～445.440,P=0.0001).肺炎的发生与术前Ⅲ级以上肝性脑病无相关性.结论 肝功能衰竭患者肝移植术后发生肺炎是导致其死亡的主要原因之一;年龄、肝肾综合征和移植肝功能不良是肝移植后发生肺炎的独立危险因素.     

Corticosteroid-free immunosuppression with daclizumab in HCV(+) liver transplant recipients: 1-year interim results of the HCV-3 study.

This work is a 1-yr interim analysis of a prospective, randomized, multicenter trial evaluating the effect of corticosteroid-free immunosuppression on hepatitis C virus-positive (HCV(+)) liver transplant recipients following liver transplantation (LT). Patients received tacrolimus and corticosteroids (Arm 1; n = 80); tacrolimus, corticosteroids, and mycophenolate mofetil (MMF) (Arm 2; n = 79); or daclizumab induction, tacrolimus, and MMF (Arm 3; n = 153). At 1 yr, 64.1%, 63.4%, and 69.4% of patients achieved the composite primary endpoint of freedom from rejection, freedom from HCV recurrence, and freedom from treatment failure, respectively. Excellent patient and graft survival did not differ significantly among treatment arms. Freedom from HCV recurrence at 1 yr was 61.8 +/- 6.2%, 60.1 +/- 6.1%, and 67.0 +/- 4.3% in Arms 1, 2, and 3, respectively (P = not significant). Freedom from rejection was significantly higher in Arm 3 compared to Arm 1 (93.0 +/- 2.2% vs. 81.9 +/- 4.4%; P = 0.011). Multivariate analysis identified acute rejection (hazard ratio = 2.692; P = 0.001) and donor age (hazard ratio = 1.015; P = 0.001) as significant risk factors for HCV recurrence. HCV recurrence was not influenced by recipient demographics, HCV genotype, or immunosuppression. In conclusion, these results suggest that a corticosteroid-free regimen of tacrolimus and MMF following daclizumab induction is safe and effective in HCV(+) liver transplant recipients.     

Combination therapy with peginterferon alpha-2B and ribavirin in liver transplant recipients with recurrent HCV infection: preliminary results of an open prospective study

Allograft reinfection with hepatitis C virus (HCV) in transplant recipients occurs commonly and represents a major concern in the transplant setting. Suppression of viral replication in HCV transplant patients should prevent or delay progression to cirrhosis and graft failure. In this ongoing study, we present preliminary data from a prospective trial of standard interferon (IFN) alpha-2b (2 million units daily) for 3 months and subsequent peginterferon (PEG IFN) alpha-2b (1.5 microg/kg/week) for 9 months. IFN therapy was combined with ribavirin (10 to 12 mg/kg). So far, HCV has become undetectable by qualitative PCR in 33% of patients while 25% had a reduction of HCV RNA to undetectable by the bDNA assay and 42% had no virological response after 6 months of therapy. A biochemical response was detected in 42% of patients. Improvement of inflammatory activity was observed in 42% of patients after 6 months. In three patients anemia necessitated administration of erythropoietin and three patients received granulocyte-colony stimulating factor (G-CSF) due to leucopenia [corrected] In conclusion, we observed that daily IFN alpha-2b and subsequent PEG IFN alpha-2b therapy in combination with ribavirin provides biochemical and virological benefits in transplant recipients with established recurrent HCV infection.     

Long-term results of pediatric liver transplantation: an analysis of 569 transplants.

OBJECTIVE: To analyze a single center's 13-year experience with 569 pediatric orthotopic liver transplants for end-stage liver disease. SUMMARY BACKGROUND DATA: Despite advances in medical therapy, liver replacement continues to be the only definitive mode of therapy for children with end-stage liver disease. Innovative surgical techniques and improved immunosuppression have broadened the application of liver replacement for affected children. However, liver transplantation in the child remains challenging because of the scarcity of donor organs, complex surgical technical demands, and the necessity to prevent long-term complications. METHODS: The medical records of 440 consecutive patients younger than 18 years of age undergoing orthotopic liver transplantation for end-stage liver disease from March 20, 1984, to November 15, 1997, were reviewed. Results were analyzed using Cox multivariate regression analysis to determine the statistical strength of independent associations between pretransplant covariates and patient and graft survival. Actuarial patient and graft survival rates were determined at 1, 3, 5, and 10 years. The type and incidence of posttransplant complications were determined, as was the quality of long-term allograft function. The median follow-up period was 4.1 years. RESULTS: Biliary atresia was the most common cause (50.4%) of endstage liver disease in this patient population. The median recipient age was 2.4 years; 239 patients (54%) were younger than 3 years of age and 1 11 patients (25%) were younger than 1 year of age. There were 471 whole organs, 29 were ex vivo reduced size, 33 were living-related donor, and 36 were in situ split-liver allografts. Three hundred forty-three (78%) patients underwent a single allograft, whereas 97 patients required retransplantation; hepatic artery thrombosis was the most common indication for retransplantation (55 patients). The 1-, 3-, 5-, and 10-year actuarial patient survival rates were 82%, 80%, 78%, and 76%, respectively; allograft survival rates were 68%, 63%, 60%, and 54%. Long-term liver function remains excellent: current median follow-up values for total bilirubin and aspartate aminotransferase were 0.5 mg/dl and 54 IU/L, respectively. Cox multivariate regression analysis demonstrated that pretransplant patient age, the era of transplantation, and the number of allografts performed significantly and independently predicted patient survival rates, whereas allograft type and pretransplant diagnosis did not. CONCLUSIONS: Liver transplantation in the pediatric patient is a durable procedure that provides excellent long-term survival. Although there have been overall improvements in patient outcome with increased experience, the effect is most pronounced for patients younger than 1 year of age. Retransplantation, although effective in a meaningful number of patients, continues to carry a progressive decrement in survival with the number of allografts performed. Use of living-related and in situ split-liver allografts has dramatically reduced waiting times for small children and has improved patient survival.     

Splitting liver transplantation. Orthotopic liver transplantation in two recipients with a single donor liver

Surgical reduction of donor livers to treat small children has been performed successfully in several centers. While this procedure improves the allocation of livers, it does not increase the organ supply. Since either lobe can be used in preparing a reduced-size graft, both lobes can become grafts, if acceptable vascular pedicles and bile ducts can be established for each one. We report and demonstrate a technique, in which a donor liver has been split and was used to transplant in two recipients.     

Human leukocyte antigen and adult living-donor liver transplantation outcomes: an analysis of the organ procurement and transplantation network database.

Human leukocyte antigen (HLA) compatibility has no clinically significant impact in cadaveric liver transplantation. Less is known regarding living-donor liver transplantation (LDLT). Our prior analysis of the Organ Procurement and Transplantation Network (OPTN) database suggested a higher graft failure rate in patients who underwent LDLT from donors with close HLA match. We further investigated the effect of HLA-A, -B, and -DR matching on 5-yr graft survival in adult LDLT by analyzing OPTN data regarding adult LDLT performed between 1998 and 2005. We evaluated associations between 5-yr graft survival and total, locus-specific, and haplotype match levels. Separate analyses were conducted for recipients with autoimmune (fulminant autoimmune hepatitis, cirrhosis secondary to autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) or nonautoimmune liver disease. Multivariable Cox proportional hazard models were used to evaluate interactions and adjust for potential confounders. Among 631 patients with available donor/recipient HLA data, the degree of HLA match had no significant effect on 5-yr graft survival, even when analyzed separately in recipients with autoimmune vs. nonautoimmune liver disease. To be able to include all 1,838 adult LDLTs, we considered a first-degree related donor as substitute for a close HLA match. We found no difference in graft survival in related vs. unrelated pairs. In conclusion, our results show no detrimental impact of close HLA matching on graft survival in adult LDLT, including in recipients with underlying autoimmune liver disease.     

Cost‐effectiveness analysis of antiviral treatment in liver transplant recipients with HCV infection

Within 5–10 years, 20–40% of hepatitis C virus (HCV)‐infected liver transplant recipients can be expected to develop cirrhosis. Here, cost‐effectiveness of antiviral therapy was assessed. A Markov model was developed to simulate disease progression and calculate outcome and costs of treatment. In the baseline analysis, Peg‐IFN/RBV treatment prevented organ loss/death, gained quality‐adjusted life‐years (QALYs) and undercut the limit of cost‐effectiveness of €50 000/QALY with an incremental cost‐effectiveness ratio of approximately €40 400/QALY and €21 000/QALY for HCV genotype 1 and 2/3 patients, respectively. Furthermore, sensitivity analysis testing modified model parameters according to extreme data described in the literature confirmed cost‐effectiveness for a lower or higher rate of fibrosis progression, increased non‐HCV‐related mortality, lower limits of utilities, a time horizon of 30 years, and additional costs in the year of death. On the other hand, cost‐effectiveness was lost for patients with genotype 1 in case of doubled antiviral or life‐time costs or an increased discount rate of 7%. New treatment strategies for HCV genotype 1 infected patients remained on the same level cost‐effective, if additional costs did not exceed €10 774 per 10% sustained virologic response gain. We conclude that Peg‐IFN/RBV treatment is cost‐effective post transplant. This may support treatment decision in individual cases.     

Modified splitting technique for liver transplantation in adult-sized recipients. Technique and preliminary results

In the common split liver technique the liver is divided between the right lobe, to be transplanted to an adult, and the left lateral segment, to be transplanted to a small child. We have developed an alternative technique by which the cadaver donor liver is divided in its two anatomo-functional halves, both apt to be transplanted to adults or children of adult size. We have so far used this technique in three multi organ donors, generating, six liver grafts that we transplanted to six recipients with median age of 36.5 years (range 10-23) and a median weight of 55 kg (range 38-79). Patient survival was 83.3% and graft survival 66.6% with a median follow up of 10 months (range 8-14). These results show that the technique is effective and that it can consistently increase the number of liver grafts that can be transplanted into adult patients, with the available cadaver donor pool.     

免疫抑制剂撤除治疗肝移植术后重症感染

目的 对肝移植术后围手术期并发重症感染患者,在检测CD4+T细胞计数及ATP数值的前提下,暂时停用免疫抑制剂,并探讨治疗的有效性和安全性.方法 根据发生重症感染后是否停用免疫抑制剂,将51例患者分为对照组(24例)和试验组(27例).试验组参考所检测CD4+T细胞及ATP数值,停用免疫抑制剂;在感染得到控制后,逐渐恢复原免疫抑制治疗方案.对患者的肝功能、急性排斥反应及存活率等进行随访监测,并观察2组患者在治疗期间发生的不良反应.结果 51例患者中39例患者痊愈,12例死亡,其中对照组死亡9例,试验组死亡3例.试验组停用免疫抑制剂的时间为6 ～22 d,平均(15.5 ±4.8)d.CD4+T细胞计数由(65.60±32.58)/μ1回升至(103.04±12.39)/μl,ATP由(79±23)μg/L回升至(112±11)μg,/L;与此同时,患者体温由38.3℃±1.2℃降至36.4℃±1.1℃,白细胞计数由(15.7±4.4)×109/L降至(6.3±3.8)×109/L,C反应蛋白由(153.4±37.1) mg/L降至(16.5±4.8)mg/L.在围手术期停用免疫抑制剂期间,未发生急性排斥反应以及肝功能恢复不良情况;试验组较对照组抗感染治疗效果好,存活例数高,且感染控制时间明显缩短(分别F=5.32,8.37,9.12,均P＜0.05).结论 可以根据CD4+T细胞计数及ATP数值量化评估肝移植受者的细胞免疫功能,在加强抗感染治疗的同时,配合撤除免疫抑制剂,有助于病情的控制.