Combination of interferon alfa-2b and ribavirin in liver transplant recipients with histological recurrent hepatitis C

Recurrent hepatitis C virus (HCV) infection is an important cause of fibrosis and cirrhosis after liver transplantation (LT), with histological recurrence developing in at least 50% of patients within the first year. The aim of this study is to assess the safety and efficacy of interferon alfa-2b plus ribavirin in treating histological recurrent HCV after LT. Since 1998, patients with HCV with significant histological recurrence (fibrosis ≥ 3 and/or histological activity index ≥ 5) or progressive cholestatic disease after LT were treated with interferon alfa-2b (3 million units subcutaneously three times weekly) plus ribavirin (800 to 1,000 mg/d) for 12 months. Immunosuppression was tapered to cyclosporine/FK506 monotherapy. HCV RNA was assessed at entry, week 24, end of treatment, and 6 months after therapy. The primary end point was loss of HCV RNA 6 months after therapy, whereas the secondary end point was histological response. Fifty-four patients met criteria for treatment and have completed follow-up. Patients were mainly men (71% men; mean age, 51 ± 5 years) with genotype 1 infection (88%) and high viral load (mean HCV RNA, 38 ± 9 mEq/mL). Dose modification was required in 72% of patients because of cytopenia or side effects. Intent-to-treat analysis showed that serum HCV RNA was undetectable in 19 patients (35%) week 24, 21 patients (38%) week 48, and 16 patients (30%) at the 6-month follow-up. Paired liver biopsy results (before and within 6 months after treatment) were available for 35 patients. Patients who achieved viral eradication had no significant progression of fibrosis after 1 year of therapy. In summary, combination therapy is a reasonable antiviral option for recurrent HCV infection for established post-LT hepatitis and appears to prevent histological progression of disease if viral eradication is successful. (Liver Transpl 2002;8:1000-1006.)     

Outcome of treatment with pegylated interferon and ribavirin in heart transplant recipients with chronic hepatitis C

Background/aim

The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) is the current treatment for chronic hepatitis C (CHC). The treatment is thought to suppress viral replication and induce viral clearance via immunomodulatory effects. For this reason, concern exists for the use of this treatment in recipients of a solid organ transplantation. We sought to evaluate the safety and efficacy of PEG-IFN/RBV in heart transplant recipients with CHC.

Methods

From June 2005 to September 2009, we treated three CHC patients with heart transplantation. PEG-IFN alpha2b and RBV doses and treatment duration were set according to the hepatitis C virus (HCV) genotype and body weight as per current recommendations. Dose reductions were dictated by individual patient tolerability. Cardiac safety was monitored by clinical examinations, echocardiography, and measurement of troponin I and B-type natriuretic peptide, as well as endomyocardial biopsies.

Results

All three patients, displayed HCV genotype 1b infection, viral loads of >5 logs, and a Scheuer fibrosis score ≥ 2. Two of them completed the prescribed treatment course becoming sustained virological responders. The other patient had an initial complete virological response, but subsequently experienced a viral breakthrough after reduction of PEG-IFN and withdrawal of RBV due to severe anemia. We observed no cardiovascular adverse events nor rejection episodes. Posttreatment clinical history and examination, electrocardiography, and echocardiography did not show any sign of graft dysfunction.

Conclusions

Treatment with PEG-IFN/RBV may be safely offered to stable heart transplant recipients with CHC and signs of liver disease progression. Close monitoring of treatment safety is mandatory.     

Pharmacokinetics of tacrolimus in living donor liver transplant and deceased donor liver transplant recipients

INTRODUCTION: Hepatic dysfunction is an important determinant of the clearance of tacrolimus; however, the impact of reduced hepatic mass in living donor liver transplant (LDLT) patients on the drug exposure and clearance of tacrolimus is not known. AIM.: The aim of the present study is to compare the dosage, concentration and pharmacokinetics parameters of tacrolimus between LDLT and deceased donor liver transplant (DDLT) recipients. PATIENTS AND METHODS: Daily doses used and trough concentrations measured were compared in 12 LDLT and 12 DDLT patients. Multiple blood samples were taken over one dosing interval after oral tacrolimus administration, and pharmacokinetics differences were compared. RESULTS: The mean tacrolimus dosage in first 14 postoperative days was (0.06 mg/kg/day) for LDLT and (0.09 mg/kg/day) for DDLT (P=0.0001). Despite the lower doses used, mean trough concentration was significantly greater in LDLT as compared with DDLT (8.8+/-2.5 ng/mL vs. 6.79+/-1.5 ng/mL, respectively, P=0.013). On the day of the pharmacokinetic study, minimum Concentration (Cmin), 12-hr postdose concentration (Clast), and average concentration (Cavg) were significantly greater in LDLT as compared with DDLT (LDLT: 6.6+/-2.4 ng/mL, 7.2+/-1.8 ng/mL, 8.9+/-3.0 ng/mL; DDLT: 4.3+/-1.0 ng/mL, 4.9+/-1.6 ng/mL, 5.9+/-1.4 ng/mL, P=0.02, 0.04, and 0.02, respectively). Dose normalized AUC was 37.7% greater and clearance, 47.5% lower in LDLT as compared with DDLT. CONCLUSION: Although not statistically significant, the dose normalized AUC was 37.7% greater and clearance 47.5% lower in LDLT as compared with DDLT. An initial tacrolimus dose reduction of about 30-40% may be prudent in LDLT compared with DDLT recipients.     

Relapse response to interferon and ribavirin in liver transplant recipient with hepatitis C recurrence

After a liver transplantation, hepatitis C virus (HCV) recurs in 90% of cases. The evolution varies according to a number of factors inherent in the host or the graft. The only therapy currently able to modify its evolution is combined interferon/ribavirin, but 22% of cases show a nonsustained response and a mere 8% achieve a sustained response. We report the case of a patient who at age 38 years underwent orthotopic liver transplantation (OLT) for HCV-related cirrhosis that developed over 7 years following blood transfusion. Following HCV recurrence at 5 years, the patient underwent 4 cycles of antiviral therapy over a 4-year period, using various protocols. First, Ribavirin alone evoked no response and the other 3 a nonsustained response. Liver biopsy after the 4th cycle showed no change in inflammation or fibrosis with respect to the biopsy performed before the first cycle. Today, at 14 years after OLT, there is still no evidence of development of cirrhosis despite immunosuppressive therapy. We suggest a benefit of repeating cycles of antiviral therapy in patients who have undergone OLT with HCV reinfection, even if they continue to show a nonsustained response but are able to tolerate the therapy.     

Weaning of immunosuppression in living donor liver transplant recipients

BACKGROUND: Some reported studies have indicated the possibility of immunosuppression withdrawal in cadaveric liver transplantation. The aim of this study was to evaluate the possibility and feasibility of weaning living donor liver transplant recipients from immunosuppression. METHODS: From June of 1990 to October of 1999, 63 patients were considered to be weaned from immunosuppression. They consisted of 26 electively weaned patients and 37 either forcibly or incidentally weaned patients (nonelective weaning) due to various causes but mainly due to infection. Regarding elective weaning, we gradually reduced the frequency of tacrolimus administration for patients who survived more than 2 years after transplantation, maintained a good graft function, and had no rejection episodes in the preceding 12 months. The frequency of administration was reduced from the conventional b.i.d. until the start of weaning to q.d., 4 times a week, 3 times a week, twice a week, once a week, twice a month, once a month, and finally, the patients were completely weaned off with each weaning period lasting from 3 to 6 months. The reduction method of nonelective weaning depended on the clinical course of each individual case. When the patients were clinically diagnosed to develop rejection during weaning, then such patients were treated by a reintroduction of tacrolimus or an additional steroid bolus when indicated. RESULTS: Twenty-four patients (38.1%) achieved a complete withdrawal of tacrolimus with a median drug-free period of 23.5 months (range, 3-69 months). Twenty-three patients (36.5%) are still being weaned at various stages. Sixteen patients (25.4%) encountered rejection while weaning at median period of 9.5 months (range, 1-63 months) from the start of weaning. All 16 were easily treated with the reintroduction of tacrolimus or additional steroid bolus therapy. CONCLUSIONS: We were able to achieve a complete withdrawal of immunosuppression in some selected patients. Although the mechanism of graft acceptance in these patients has yet to be elucidated, we believe that a majority of long-term patients undergoing living donor liver transplantation may, thus, be potential candidates to be successfully weaned from immunosuppression.     

Successful treatment of HCV-related cryoglobulinemic glomerulonephritis with double-filtration plasmapheresis and interferon combination therapy

A 67-year-old, hepatitis C virus (HCV)-positive woman was admitted to our hospital because of proteinuria and leg edema. Laboratory examination showed decreased serum albumin and complement activity and positive cryoglobulin. The HCV RNA genotype was 1b with high viral load. Kidney biopsy showed membranoproliferative glomerulonephritis (MPGN) with capillary deposition of C3, IgM, and IgG, indicating HCV-associated glomerulonephritis. In addition to interferon (IFN) therapy, double-filtration plasmapheresis (DFPP) was performed to reduce HCV RNA blood levels in the early stage of IFN therapy. This treatment greatly reduced the viral load and induced clinical remission of MPGN, suggesting that DFPP plus IFN combination therapy may represent a potentially effective modality for refractory-type HCV-associated glomerulonephritis.     

Successful rescue of severe recurrent hepatitis C with interferon and ribavirin in a liver transplant patient

BACKGROUND: Rapid graft dysfunction caused by hepatitis C virus (HCV) reinfection, although uncommon, is a disastrous complication in liver transplant patients. Finding an effective therapy for this subgroup of patients with severe recurrent HCV is a priority. METHOD: We describe a successful rescue of a 46-year-old man with recurrent hepatitis C (HCV genotype 1b) using long-term interferon (IFN) and ribavirin. The patient had a very aggressive type of posttransplantation HCV infection, as judged by biochemical and histologic findings. RESULTS: Despite high pretreatment values of serum alanine aminotransferase (ALT; peak value of 901 IU/L) and HCV-RNA (2.3 x 10(6) copies/ml), the combination therapy with IFN and ribavirin produced a rapid normalization of the serum ALT values, accompanied by the clearance of serum HCV-RNA. Although HCV-RNA reappeared in the serum at 3 months, the patient had continued ALT normalization and histological improvement with follow-up of over 26 months to date after the initiation of the combination therapy. CONCLUSION: This observation suggests that IFN in combination with ribavirin may offer an effective therapeutic option for liver transplant patients with severe recurrent hepatitis C.     

Neurologic complications in adult living donor liver transplant recipients

BACKGROUND: Neurologic complications (NC) after liver transplantation are not uncommon, with serious complications such as central pontine myelinolysis (CPM), often causing disability. OBJECTIVE: We investigated the incidence and features of NC following liver transplantation in adult recipients. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 319 adult patients who underwent liver transplantation between January 2004 and May 2005 at the Asan Medical Center. RESULTS: Neurologic complications developed in 49 of 319 patients (15.4%). Although most of these complications were minor, including tremor and foot drop, three patients developed CPM, and one each developed posterior leukoencephalopathy, cerebral hemorrhage, and cerebral infarction. One-yr survival rates were 95.9% in patients without NC and 83.7% in patients with NC (p = 0.004). Hospital stay was prolonged in patients with NC. Graft-to-recipient body weight ratio (GRWR) did not affect occurrence of NC. CONCLUSIONS: Neurologic complications were not uncommon in liver transplant recipients. These complications contributed to prolongation of hospital stay, increased in-hospital mortality, and decreased graft and patient survival. Every effort should be made to prevent NC, as well as to detect and treat them as soon as possible.     

Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation.

In this retrospective study of hepatitis C virus (HCV)-infected transplant recipients in the 9-center Adult to Adult Living Donor Liver Transplantation Cohort Study, graft and patient survival and the development of advanced fibrosis were compared among 181 living donor liver transplant (LDLT) recipients and 94 deceased donor liver transplant (DDLT) recipients. Overall 3-year graft and patient survival were 68% and 74% in LDLT, and 80% and 82% in DDLT, respectively. Graft survival, but not patient survival, was significantly lower for LDLT compared to DDLT (P = 0.04 and P = 0.20, respectively). Further analyses demonstrated lower graft and patient survival among the first 20 LDLT cases at each center (LDLT 20; P = 0.002 and P = 0.002, respectively) and DDLT recipients (P < 0.001 and P = 0.008, respectively). Graft and patient survival in LDLT >20 and DDLT were not significantly different (P = 0.66 and P = 0.74, respectively). Overall, 3-year graft survival for DDLT, LDLT >20, and LDLT 20 were not significantly different. Important predictors of graft loss in HCV-infected patients were limited LDLT experience, pretransplant HCC, and higher MELD at transplantation.     

Effect of donor age on survival of liver transplant recipients with hepatitis C virus infection

BACKGROUND: Chronic hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation (OLT) in the United States. Recent studies from selected centers have suggested that older donor age is associated with worse outcomes after transplantation for HCV. METHODS: We analyzed the United Network for Organ Sharing Liver Transplant Registry database from April 1987 to March 2003 to examine predictors of death or retransplantation in patients with HCV. Univariate models for each predictor were evaluated. Factors significant in the univariate model were used to develop a multivariable model. RESULTS: Of 6,956 patients meeting the inclusion/exclusion criteria, 1,527 (22.0%) died or received retransplants during the first year after transplant. Recipients with graft failure were older, had greater serum creatinine levels, and were more likely to require mechanical ventilation and hemodialysis before transplant. Donors of patients with graft failure were older and more likely to have diabetes mellitus. In the multivariable regression model, predictors of graft failure at 1 year were donor age, recipient age, recipient creatinine greater than 2 mg/dL, and the requirement for mechanical ventilation for the recipient. CONCLUSIONS: Both older donor age and older recipient age plus markers of severity of disease, including requirement for mechanical ventilation and renal insufficiency, are negatively associated with survival after liver transplantation. These factors should be considered when assessing OLT recipient and donor candidacy in patients with HCV.     

Impact of late conversion from C0 to C2 monitoring of microemulsified cyclosporine in pediatric living donor liver transplant recipients

The efficacy and feasibility of 2-h post-dose level (C2) monitoring of cyclosporine in long-term living donor liver transplantation (LDLT) is not clear. The aim of this study was to investigate the impact of late conversion from conventional trough-level (C0) monitoring to C2 monitoring of a microemulsion form of cyclosporine (Neoral) in pediatric LDLT recipients. From June 1994 to August 2002, we performed 116 LDLTs in 115 patients. Initially, we adapted conventional C0 monitoring of Neoral, which was converted to C2 monitoring starting in January 2002. The 60 patients who were enrolled in the study had the following characteristics: they were younger than or equal to 15 yr at transplantation, and they had survived LDLT, and they had received a Neoral-based immunosuppression regimen, and they underwent conversion to C2 more than 1 month after transplantation. We evaluated the impact of conversion on doses, blood levels, rejection, adverse effects, and patient/graft outcome. In the long-term patients, the mean C2 levels immediately after conversion were higher than the target levels at any time point selected after transplantation; thus, 34 patients (57%) finally required a dose reduction of Neoral. The current mean C2 level was significantly lower than that observed immediately after conversion (584.6 +/- 262.8 ng/ml vs. 893.1 +/- 260.2 ng/ml, mean +/- SD, p < 0.0001) with a mean follow-up period of 7.4 +/- 0.6 months (range: 5-8 months) after conversion. Only one patient encountered rejection after conversion (1.7%), and no de novo infection or adverse effects were observed. Traditional C0 monitoring of Neoral was safely replaced by C2 monitoring without an increase in the rejection rate or any adverse effects in pediatric LDLT patients. C2 monitoring contributed to the dose reduction of Neoral, which may lead to the avoidance of long-term complications due to immunosuppression.     

聚乙二醇化干扰素联合利巴韦林治疗肝移植术后丙型肝炎复发

目的 探讨聚乙二醇化干扰素(PEG-IFNα)联合利巴韦林治疗肝移植术后丙型肝炎复发的效果及安全性.方法 回顾性分析9例丙型肝炎相关终末期肝病患者接受肝移植的临床资料,其中5例受者术后出现丙型肝炎复发,均给予PEG-IFNα-2a联合利巴韦林抗HCV治疗,疗程为48周.观察治疗前后血红蛋白、白细胞计数、移植肝功能及HCV RNA复制水平等指标的变化,评估治疗后的早期病毒应答(EVR)、持续性病毒应答(SVR)及不良反应等.结果 5例受者中有3例在治疗12周内达到EVR,并在治疗后获得SVR,移植肝功能也恢复正常;1例因在治疗12周后HCVRNA的下降达不到2个对数级而停药,1例虽HCV RNA下降2个对数级以上,但治疗至24周时HCV RNA未转阴而停药,至48周时HCV RNA均维持在较低水平.5例丙型肝炎复发受者在治疗后均发生白细胞减少和(或)发热等不良反应,给予对症处理后好转.结论 PEG-IFNα联合利巴韦林治疗肝移植后丙型肝炎复发安全性好,多数受者可取得持续性病毒学应答.     

New prognostic model for adult-to-adult living donor liver transplant recipients

Adult-to-adult living donor liver transplantation (A-A LDLT) is an effective therapeutic modality to treat patients with end-stage liver disease. The aims of this study were to identify recipient characteristics of A-A LDLT seeking to determine variables that affected patient survival. We retrospectively examined a cohort of 154 consecutive A-A LDLT recipients with end-stage liver disease in our center over 4 years. All donors volunteered to give their partial livers with written consent. There were no organs from prisoners and no prisoner subjects. The overall survivals at 1, 2, 3, 6, 12, 24, 36, and 48 months were 93.5%, 90.9%, 88.9%, 86.3%, 80%, 65.6%, 63.8%, and 63.8%, respectively. About 31 pre- and intraoperative factors were analyzed to identify correlations with posttransplant survival using the Cox proportional-hazards regression model. Recipient age, serum creatinine concentration, intraoperative blood loss, and graft-to-recipient weight ratio were significant predictors of survival after transplantation. The prognostic index model, which was calculated by combining these four prognostic values with their regression coefficients, showed a c-statistic of 0.706 (95% confidence interval [CI] = 0.621-0.792) compared with the Model for End-stage Liver Disease value of 0.546 (95% CI = 0.350-0.558). There was a significant difference between the predictions achieved with the two models (P = .012). In conclusion, selecting younger recipients, better pretransplant renal condition, reduced intraoperative blood loss, and graft-to-recipient size match appeared to be advantageous to achieve better survivals among patients undergoing A-A LDLT.     

Tacrolimus dosing requirements and concentrations in adult living donor liver transplant recipients

Living donor liver transplantation in adult recipients is becoming increasingly common. The liver metabolizes most drugs, including immunosuppressive agents. Right-lobe grafts used in adult living donor liver transplantation consist of only 50% to 60% of the total liver. The purpose of this study is to determine whether there is a difference between tacrolimus doses and concentrations in patients who received a partial liver transplant from a living donor (LRD) versus those who received a whole-liver transplant from a cadaveric donor (CAD). Thirteen LRD recipients and 13 CAD recipients who underwent transplantation between April 1998 and July 2000 were included in this analysis. A CAD control group matched for age, sex, and race was used for comparison. Tacrolimus doses and concentrations were analyzed weekly for the first 4 weeks, then monthly for 6 months posttransplantation. There was no difference in acute rejection rates, renal and liver function test results, or number of potentially interacting medications administered between groups. LRD recipients required significantly lower doses of tacrolimus compared with CAD recipients at 2 weeks (0.058 v 0.110 mg/kg/d; P [lt ] .01), 3 weeks (0.068 v 0.123 mg/kg/d; P [lt ] .02), 4 weeks (0.086 v 0.141 mg/kg/d; P [lt ] .02), 2 months (0.097 v 0.141 mg/kg/d; P [lt ] .03), and 3 months (0.099 v 0.138 mg/kg/d; P [lt ] .03). Tacrolimus 12-hour trough concentrations were similar between groups at all times except for 2 weeks posttransplantation, when LRD recipients' concentrations were significantly greater than those of CAD recipients (12.4 v 9.5 ng/mL; P [lt ] .03). In addition, in the first month posttransplantation, LRD recipients were more likely to have greater concentrations of tacrolimus ([gt ]15 ng/mL; 22.1% v 9.2%; P [lt ] .01). In conclusion, LRD recipients have significantly decreased tacrolimus dosing requirements compared with CAD recipients during the first 3 months posttransplantation despite having similar tacrolimus concentrations. (Liver Transpl 2002;8:219-223.)     

Intraoperative fluid management of living donor versus cadaveric liver transplant recipients

Living donor liver transplantation has increasingly become an alternative to cadaveric donor liver transplants for select adult patients. Because these cases can be performed electively, living donor recipients may have better compensated liver disease at the time of surgery than cadaver donor recipients. However, it is unknown if this difference would have a significant effect on their intraoperative course. Therefore, we compared the intraoperative fluid management of patients receiving liver grafts from either living or cadaveric donors (n = 25, each group). Patient groups did not differ in demographics or baseline laboratory values. The duration of anesthesia and anhepatic phases were significantly longer in living donor cases (651 +/- 80 minutes vs 409 +/- 20 and 55 +/- 14 vs 45 +/- 6, P < .05). Adjusted for anesthesia time and patient weight, fluid administration (crystalloid and albumin) was not different between the two groups. Intraoperative transfusion requirements were also not significantly different in recipients from living donors versus cadaveric donors with regard to red blood cells, fresh frozen plasma, platelets, and cryoprecipitate. However, arterial oxygenation was better preserved in recipients from living donors. The PaO2/FiO2 (P/F) ratio at the end of the procedure was significantly better in patients receiving livers from living rather than from cadaveric donors (P/F ratio 335 +/- 114 mm Hg vs 271 +/- 174, P < .05). Our results indicate that while intraoperative fluid and transfusion requirements are similar, the impact of transplantation on pulmonary gas exchange is more pronounced in patients receiving organs from cadaveric donors. This difference may arise from longer cold ischemia times present in the cadaveric donor group.     

Occult hepatitis B virus infection in liver transplant recipients with recurrent hepatitis C: relationship with donor age and fibrosis progression

Abstract:  Liver transplantation (OLT) recipients who receive a graft from donors positive for hepatitis B virus (HBV) anti-core antibodies may develop overt " de novo " HBV infection. The study was undertaken to explore how often HBV infection may remain occult after OLT for hepatitis C, and whether it may represent a factor of graft fibrosis progression. We studied 30 consecutive patients transplanted for hepatitis C liver disease. Specimens from the native liver and from the graft were searched for occult HBV infection (O-HBV). In the native liver, 8/30 patients had detectable O-HBV; during the follow-up, O-HBV infection was demonstrated in 14 graft specimens. Graft O-HBV was associated with older donor age (≥50 yr; 8/9 vs. 6/21, p < 0.005). Recipients with graft O-HBV and no O-HBV in the native liver who received their grafts from donors aged >40 yr had faster fibrosis progression than recipients with no post-transplant O-HBV, whose grafts came from donors aged >40 yr and recipients whose grafts came from donors aged ≤40 yr (4/7 vs. 1/7 vs. 2/16, p < 0.05). In OLT recipients, O-HBV is more likely to occur when grafts are obtained from aged donors and may affect the rate of fibrosis progression because of recurrent hepatitis C.     

Risk factors for invasive aspergillosis in living donor liver transplant recipients.

Invasive aspergillosis (IA) is a severe complication of liver transplantation. Risk factors for IA after deceased donor liver transplantation (DDLT) have been presented in several reports, but are not well established for living donor liver transplant recipients. Here, a retrospective case-control study was performed. Five cases with IA were investigated after living donor liver transplantation (LDLT) between January 1999 and December 2002 at Kyoto University Hospital. For comparison, living donor liver transplant recipients without IA were taken as controls. These patients had undergone LDLT 1 month before or after each IA case and had the same survival times as the latter. We evaluated the clinical and laboratory findings for both groups up until their demise. Patients with IA after LDLT had a very poor prognosis. By univariate analysis, risk factors for IA were preoperative intensive care unit stay (P = 0.02) and preoperative steroid administration (P = 0.02). Preoperative steroid administration for fulminant hepatitis possibly predisposed to the development of IA after LDLT.